ES2567753T3 - Derivatives of 1,2,4-thiazolidin-3-one and their use in the treatment of cancer - Google Patents

Abstract

A compound of formula I, ** Formula ** in which: A represents C (> = N-W-D) or S; B represents S or C (-NH-W-D); when: A represents C (> = N-W-D) and B represents S, then the dashed line between B and the N atom is a single bond; or A represents S and B represents C (-NH-W-D), then the broken line between B and the N atom is a double bond; X represents -Q- [CRxRy] n-; W represents- [CRxRy] m- or -C (O) - [CRxRy] p-; Q represents a bond, -N (Ra) -, -S- or -O-; A1 to A5 respectively represent C (R1), C (R2), C (R3), C (R4) and C (R5), or, alternatively, up to two of A1 to A5 may independently represent N; D represents phenyl, pyridyl or pyrimidinyl optionally substituted with one or more R6 groups; Rx and Ry, each time used herein, are independently selected from H, halogen, C1-6 alkyl (optionally substituted with one or more halogen atoms), aryl (optionally substituted with one or more halogen atoms ) or Rx and Ry are linked to form, together with the carbon atom to which they are attached, a 3 to 8 membered non-aromatic ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is the same optionally substituted with one or more substituents selected from halogen or C1-6 alkyl (optionally substituted with one or more halogen atoms); R1 to R5 independently represent H, halogen, -R7, -CF3, -CN, -NO2, -C (O) R7, -C (O) OR7, -C (O) - N (R7a) R7b, -N ( R7a) R7b, -N (R7) 3 +, -SR7, -OR7, -NH (O) R7, -SO3R7, aryl or heteroaryl (these same aryl and heteroaryl groups are optionally and independently substituted with one or more groups selected from halogen and R16), or any two of R1 to R5 that are adjacent to each other, are optionally linked to form, together with two atoms of the essential benzene ring in the compound of formula I, an aromatic or non-aromatic ring from 3 to 8 members, optionally containing 1 to 3 heteroatoms selected from O, S and N, the ring itself optionally substituted with one or more substituents selected from halogen, -R7, -OR7 and> = O; R6 independently represents, at each occurrence used herein, cyano, -NO2, halogen, -R16, -OR8, -N (R8) C (O) R8, -NR9R10, -SR11, -Si (R12) 3, -OC (O) R13, -C (O) OR13, -C (O) R14, -C (O) NR15aR15b, -S (O) 2NR15cR15d, aryl or heteroaryl (these same aryl and heteroaryl groups are optional and independently substituted with one or more groups selected from halogen and R16), or any two R6 groups that are adjacent to each other, are linked to form, together with two atoms of the essential benzene ring in the compound of formula I, an aromatic ring or 3 to 8 membered non-aromatic, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted with one or more substituents selected from halogen, -R7, -OR7 and> = O; R7, each time used herein, is selected from H or C1-C6 alkyl, C1-C6 cycloalkyl, aryl, and heteroaryl (wherein the last four groups are optionally substituted with one or more halogen atoms); R7a and R7b are independently selected from H, or C1-C6 alkyl, C1-C6 cycloalkyl, aryl and heteroaryl, or R7a and R7b are optionally linked to form, together with the nitrogen atom to which they are attached, an aromatic or non-aromatic ring 3 to 8 membered aromatic, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted with one or more substituents selected from halogen, -R7, -OR7 and> = O; Ra, R8, R9, R10, R11, R12, R13, R14, R15a, R15b, R15c, and R15d, each time used herein, independently represent H or R16; R16 represents, on each occasion used herein, C1-6 alkyl optionally substituted with one or more halogen atoms; n represents 1 or 2;

Description

image 1

DESCRIPTION

Derivatives of 1,2,4-thiazolidin-3-one and their use in the treatment of cancer

5 Field of the invention

This invention relates to pharmaceutically useful compounds. The invention also relates to such compounds for use in the treatment of cancer.

10 Background of the invention

AMP-activated protein kinase (AMPK) represents a new target for the treatment of several diseases including cancer.

15 Excessive adiposity is associated with different degrees of increased risk of developing cancer, such as colorectal adenomas, breast cancer (postmenopausal), endometrial cancer, kidney cancer, esophageal adenocarcinoma, ovarian cancer, prostate cancer, cancer pancreatic, gallbladder cancer, liver cancer, and cervical cancer (Calle and Kaaks (2004), Nature Reviews Cancer, 4, 579-591).

20 Research has shown that cancer cells require high rates of fatty acid and protein synthesis for invasive growth and survival. Studies have shown that it is possible to inhibit cancer cell proliferation using AMPK activators. The effects are associated with negative regulation of mTOR and eEF2. AMPK activators also suppress lipid synthesis in tumor cells. A link has also been shown between AMPK and other cancer targets, such as LKB1 activation and

25 caspase 3.

Cancer cells use glucose at a higher rate compared to normal cells (Warburg O, 1956). Instead of mitochondrial oxidative phosphorylation to produce ATP, cancer cells metabolize glucose through hydrolysis.

30 Recent studies suggest that hyperinsulinemia is correlated, among other things, with the incidence of colon cancer and fatal breast and prostate cancer.

Elevation of free fatty acids (FFA) in plasma stimulates pancreatic β cells and is a cause of hyperinsulinemia.

In prostate cancer, hyperinsulinemia has been shown to be a prospective risk factor for death and data support that insulin level could be used as a marker of prostate cancer prognosis (Hammarsten and Högstedt (2005), European Journal of Cancer, 41, 2887).

40 Several mechanisms can link hyperinsulinemia with the incidence and outcome of breast cancer. First, chronic hyperinsulinemia increases the production of testosterone and estrogen in the ovary and inhibits the liver's production of sex hormone-binding globulin, a profile of sex hormones that is associated with breast cancer. Second, hyperinsulinemia suppresses hepatic production of protein 1 of

45 binding insulin-like growth factor (IGFBP-1), and thus increases circulating levels of IGF1, which has a potent mitogenic effect on breast tissue. Third, insulin itself can have a direct mitogenic effect on breast cancer cells.

The study by Hardy et al. ((2005), J. Biol. Chem. 280, 13285) shows that FFAs directly stimulate the

Growth of breast cancer cells in a GPR40-dependent manner. Furthermore, expression studies performed on isolated tumor tissue from 120 breast cancer patients show frequent expression of GPR40, emphasizing the clinical relevance of Hardy's findings (see for example Ma et al., Cancer Cell (2004) 6, 445).

55 Another expression study on clinical material from colon cancer patients suggests that similar mechanisms could also be relevant in this malignancy (see http://www.ncbi.nlm.nih.gov /projects/geo/gds/gds_browse.cgi ? gds = 1263).

In general, cancer cells show aberrant metabolism compared to non-cells.

60 transformed. Neoplastic cells synthesize lipids to a much greater extent than their normal counterparts and metabolize glucose differently. This aberrant metabolism has been suggested as a therapeutic target. By altering one or, preferably, several of the pathways that control cellular metabolism, cancer cells would be more sensitive than non-transformed cells, thus creating a therapeutic window. Examples of pathways / targets include agents that affect glycolysis, the lipid synthesis pathway, agents that activate

65 AMPK and Agents Affecting Mitochondrial Function.

image2

AMP-activated protein kinase (AMPK) is a protein kinase enzyme that consists of three protein subunits and is activated by hormones, cytokines, exercise, and stress, which decrease cellular energy status (eg, glucose deprivation). AMPK activation increases processes that generate adenosine 5'-triphosphate (ATP) (for example, fatty acid oxidation) and represses others, such as the synthesis of fatty acid, glycerolipid

5 and protein, which consume ATP, but are not strictly necessary for survival. Conversely, when cells encounter a sustained excess of glucose, AMPK activity decreases and fatty acid, glycerolipid, and protein synthesis increases. Therefore, AMPK is a protein kinase enzyme that plays an important role in cellular energy homeostasis. Therefore, AMPK activation is coupled with glucose-lowering effects and activates other biological effects including inhibition of cholesterol synthesis, lipogenesis, triglyceride synthesis, and reduction of hyperinsulinemia.

Given the above, AMPK is a preferred target for the treatment of metabolic syndrome, and especially for type 2 diabetes. AMPK is also involved in several pathways that are important for many different diseases (for example, AMPK is also involved on various routes that are important in

15 CNS disorders, fibrosis, osteoporosis, heart failure and sexual dysfunction).

AMPK is also involved in several pathways that are important in cancer. Several tumor suppressors are part of the AMP pathway. AMPK acts as a negative regulator of the mammalian TOR pathway (mTOR) and EF2, which are key regulators of cell growth and proliferation. Therefore, the imbalance can be associated with diseases such as cancer (and also diabetes). Therefore, AMPK activators may be useful as anticancer drugs.

Current antidiabetic drugs (eg metformin, glitazone) are known to be not significantly potent activators of AMPK, but only activate AMPK indirectly and with low efficacy. Nevertheless,

Due to the biological effects of AMPK activation in the cell, compounds that are activators of AMPK, and preferably direct activators of AMPK, may have utility as anticancer drugs and also for the treatment of many other diseases.

The mention or exposition in this specification of an apparently previously published document is not necessarily taken as an acknowledgment that the document is part of the state of the art or of the common general knowledge thereon.

Various publications, patents, and published patent specifications are referenced throughout this disclosure by means of an identifying citation.

35 Keilen et al., Acta Chem. Scand. 1988, B42, 362-366, describe the formation of activated 1,2,4-thiadiazolo pyrimidinones. A specific 1,2,4-thiadiazol-3-one is also disclosed. However, the document does not disclose any biological effects associated with the disclosed compounds, nor does it disclose 1,2,4-thiadiazol-3-ones substituted at the 5-position with an amide or amine derivative bearing at least one substituted aromatic ring. .

Kaugars et al., J. Org. Chem. 1979, 44 (22), 3840-3843, describe 5-phenyl- and 5-methyl-substituted phenylurea derivatives of 1,2,4-thiadiazol-3-one, which are substituted at the 2-position with a group methyl. No biological effect associated with the disclosed compounds is mentioned.

45 Cho et al. J. Heterocyclic Chem. 1991, 28, 1645-1649, disclose various 1,2,4-thiadiazol-3-ones. However, no such 1,2,4-thiadiazol-3-ones is disclosed in which the 2-position and 5-position contain substituents that carry an aromatic ring.

US Patent No. 4,093,624 describes 1,2,4-thiadiazolidin-3-one compounds having antimicrobial activity, which are substituted with an -NH2 or NHAc at the 5-position, and H or ribofuranosyl at the 5-position. position 2. There is no disclosure of 1,2,4-thiadiazol-3-ones in which position 2 and position 5 contain substituents that carry an aromatic ring.

Castro et al., Bioorg. Med. Chem. 2008, 16, 495-510, describe thiazolidinone derivatives as GSK inhibitors

55 3β that are potentially useful for the treatment of Alzheimer's disease. There is no mention that such compounds can be useful as activators of AMPK. Furthermore, there is no disclosure of such 5-substituted 1,2,4-thiadiazol-3ones with an amide or amine derivative bearing at least one substituted aromatic ring.

Martinez et al. Bioorg. Med. Chem. 1997, 7, 1275-1283 describe arilimino-1,2,4-thiadiazolidinone derivatives as potassium channel openers that are potentially useful for the treatment of diseases including smooth muscle contraction (eg hypertension) . However, there is no disclosure of 2-substituted thiazolidinones with an aromatic group.

US Patent Application Publication No. 2003/0195238 describes thiadiazolidine derivatives as GSK-3β inhibitors that are potentially useful for the treatment of Alzheimer's disease. Without

image3

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

55

60

However, this document is primarily concerned with thiadiazolidines substituted with two carbonyl / thiocarbonyl groups (thereby forming a 3,5-thiadiazolidine or 3-thioxo-5-oxo-thiadiazolidine). Furthermore, it mainly refers to compounds in which the two nitrogen atoms of thiadiazolidine are substituted. The document does not refer to thiadiazolidines substituted at the 2-position with a group bearing an aromatic group and at the 5-position with an amino or amido derivative bearing an aromatic ring.

International patent applications WO 2007/010273 and WO 2007/010281 both disclose, for example, thiazolidin-4-one and 1,1-dioxo-1,5-dihydro- [1,4,2] dithiazole compounds which are capable of antagonizing the stimulatory effect of FFA on cell proliferation when tested in an assay using a human breast cancer cell line (MDA-MB-231). Therefore, such compounds are indicated in the treatment of cancer or as modulators of FFA. However, these documents do not disclose or suggest thiadiazolidinones. L'Abbé et al., J. Hetero. Chem., 27 (4), 1990, 1059 is entitled "1,3-dipolar cycloadditions of alkyl azides with picryl isothiocyanate: isolation of stable monoadducts".

Detailed description of the invention

According to embodiments of the invention, there is provided a compound of formula I as defined in Claim 1. Also disclosed is a compound of formula I,

image4 TO

AX A1 NB

2

I

N

AA

3 h

TO

4 O

in which:

A represents C (= N-W-D) or S; B represents S or C (-NH-W-D); when:

A represents C (= N-W-D) and B represents S, then the bond between B and the NH atom is a single bond; or A represents S and B represents C (-NH-W-D), then the bond between B and the NH atom is a double bond; X represents -Q- [CRxRy] n-; W represents - [CRxRy] m- or -C (O) - [CRxRy] p-; Q represents a bond, -N (Ra) -, -S-, or -O-; A1 to A5 respectively represent C (R1), C (R2), C (R3), C (R4) and C (R5), or alternatively up to two of A1 to A5 can independently represent N; D represents phenyl, pyridyl, pyrimidinyl optionally substituted with one or more R6 groups; Rx and Ry, each time used herein, are independently selected from H, halogen, C16 alkyl (optionally substituted with one or more halogen atoms), aryl (optionally substituted with one or more halogen atoms), or Rx and Ry are linked to form, together with the carbon atom to which they are attached, a 3 to 8 membered non-aromatic ring optionally containing 1 to 3 heteroatoms selected from O, S and N, this same ring optionally substituted with one or more substituents selected from halogen or C16 alkyl (optionally substituted with one or more halogen atoms); R1 to R5 independently represent H, halogen, -R7, -CF3, -CN, -NO2, -C (O) R7, -C (O) OR7, -C (O) N (R7a) R7b, -N (R7a ) R7b, -N (R7) 3+, -SR7, -OR7, -NH (O) R7, -SO3R7, aryl or heteroaryl (these same aryl and heteroaryl groups optionally and independently substituted with one or more groups selected from halogen and R16), or any two of R1 to R5 that are adjacent to each other are optionally bonded to form, together with two essential benzene ring atoms in the compound of formula I, a 3- to 8-membered aromatic or non-aromatic ring containing optionally 1 to 3 heteroatoms selected from O, S and N, this same ring optionally substituted with one or more substituents selected from halogen, -R7, -OR7 and = O; R6 represents, independently on each occasion used herein, cyano, -NO2, halogen, -R8, -OR8, -N (R8) C (O) R8, -NR9R10, -SR11, -Si (R12) 3, -OC (O) R13, -C (O) OR13, -C (O) R14, C (O) NR15aR15b, -S (O) 2NR15cR15d, aryl or heteroaryl (these same aryl and heteroaryl groups optionally and independently substituted with one or more groups selected from halogen and R16), or any two R6 groups that are adjacent to each other are optionally linked to form, together with two essential benzene ring atoms in the compound of formula I, an aromatic or non-aromatic ring 3 to 8 membered optionally containing 1 to 3 heteroatoms selected from O, S and N, this same ring optionally substituted with one or more substituents selected from halogen, -R7, -OR7 and = O; R7, each time used herein, is selected from H or C1-C6 alkyl, C1-C6 cycloalkyl, aryl, and heteroaryl (wherein the last four groups are optionally substituted with one or more

image5

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

55

60

65

halogen atoms); R7a

and R7b are independently selected from H, or C1-C6 alkyl, C1-C6 cycloalkyl, aryl, and heteroaryl, or R7a

and R7b are optionally linked to form, together with the nitrogen atom to which they are attached, a 3- to 8-membered aromatic or non-aromatic ring optionally containing 1 to 3 heteroatoms selected from O, S and N, this same substituted ring optionally with one or more substituents selected from halogen, -R7, -OR7 and = O;

Ra R8 R12 R13 R14, R15a, R15b, R15c and R15d

,, R9, R10, R11,,,, each time used herein, independently represent H or R16; R16, each time used herein, represents C16 alkyl optionally substituted with one or more halogen atoms; n represents 0 or, more preferably, 1 or 2; m represents 2 or, more preferably, 1 or 0; p represents 2 or, more preferably, 1 or 0;

or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof; provided that when D is phenyl, then at least one of A1 to A5 is not (C-H) and / or D is substituted with one or more -R6 groups.

The pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example, by reacting a free acid or free base form of a compound of formula I, with one or more equivalents of an appropriate acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of said solvent or said medium using standard techniques (for example, vacuum, freeze-drying or filtration). Salts can also be prepared by exchanging a counterion of a compound of formula I in salt form with another counterion, for example using a suitable ion exchange resin.

Examples of pharmaceutically acceptable addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acid; from organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulfonic acid; and of metals, such as sodium, magnesium or, preferably, potassium and calcium.

"Pharmaceutically functional derivatives" of compounds of formula I, as defined herein, include ester derivatives and / or derivatives that have or provide the same biological function and / or activity as any relevant compound. Therefore, for the purposes of this invention, the term also includes the prodrugs of the compounds of formula I.

The term "prodrug" of a relevant compound of formula I includes any compound that, after oral or parenteral administration, is metabolized in vivo to form that compound in an experimentally detectable amount and over the course of a predetermined time (for example during an administration interval of between 6 and 24 hours (that is, one to four times a day)). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration.

Prodrugs of compounds of formula I can be prepared by modifying the functional groups present in the compound, such that the modifications are undone in vivo when such a prodrug is administered to a mammalian subject. Modifications are usually accomplished by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds of formula I in which a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group of a compound of formula I is attached to any group that can be removed in vivo to regenerate the hydroxyl, amino, sulfhydryl, carboxy group. or free carbonyl, respectively.

Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters of carboxyl functional groups, N-acyl derivatives, and N-Mannich bases. General information on prodrugs can be found for example in Bundegaard, H. "Design of Prodrugs" p. 1-92, Elsevier, New York-Oxford (1985).

For the sake of brevity, the compounds of formula I as defined in Claim 1 as well as the salts and solvates of such compounds are hereinafter collectively referred to as "the compounds of formula I".

Compounds of formula I can contain double bonds and therefore can exist as E (entgegen) and Z (zusammen) geometric isomers around each individual double bond. All of these isomers and their mixtures are included within the scope of the invention.

Compounds of formula I can exist as regioisomers and can also exhibit tautomerism. All tautomeric forms and their mixtures are included within the scope of the invention. For example, the following tautomers are included within the scope of the invention:

image6

FC image7 image8

3

FC image9 image10

3

Cl

Cl

Cl

Cl

The compounds of formula I contain one or more asymmetric carbon atoms and therefore can show optical isomerism or diastereoisomerism. The diastereoisomers can be separated using conventional techniques, for example chromatography or fractional crystallization. The various stereoisomers can be isolated by separating a racemic or other mixture of compounds using conventional techniques, for example fractional crystallization or HPLC. Alternatively, the desired optical isomers can be made by reacting the optically active starting materials under conditions that do not cause racemization or epimerization (ie, a "chirality pool" method), by reacting the appropriate starting material with a

10 "chiral auxiliary" which can subsequently be removed in a suitable step, by modification (ie, a resolution that includes dynamic resolution), for example with a homochiral acid, followed by separation of the diasteromeric derivatives by conventional means, such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst, all under conditions known to those skilled in the art. All stereoisomers and their mixtures are included within the scope of the invention.

Unless otherwise indicated, the term "alkyl" refers to an unbranched or branched, cyclic, saturated or unsaturated hydrocarbyl radical (thus forming for example an alkenyl or alkynyl), which may be unsubstituted or be substituted (for example with one or more halogen atoms). When the term "alkyl" refers to an acyclic group, it is preferably C110 alkyl, and most preferably C16 alkyl (such as ethyl, propyl (for

For example n-propyl or isopropyl), butyl (for example branched or unbranched butyl), pentyl or, more preferably, methyl). When the term "alkyl" is a cyclic group (which can be when the group "cycloalkyl" is specified), it is preferably C312 cycloalkyl, most preferably C510 cycloalkyl (eg C57).

When used herein, "alkylene" refers to C110 (for example C16) alkylene, and preferably

C13 alkylene, such as pentylene, butylene (branched or unbranched), preferably propylene (n-propylene or isopropylene), ethylene, or more preferably methylene (ie, -CH2-).

The term "halogen", when used herein, includes fluorine, chlorine, bromine, and iodine.

The term "aryl", when used herein, includes C614 aryl groups (such as C613 (eg C610)). Such groups can be monocyclic, bicyclic or tricyclic and can have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic. The point of attachment of the aryl groups can be through any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are attached to the rest of the molecule by an aromatic ring. C614 aryl groups include phenyl, naphthyl, etc., such as

1,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. The most preferred aryl groups include phenyl.

The term "heteroaryl" used herein refers to an aromatic group containing one or more heteroatoms (for example, one to four heteroatoms) preferably selected from N, O and S (thus forming, for example, a group monocyclic, bicyclic or tricyclic heteroaromatic). Heteroaryl groups include those with between 5 and 14 members (eg 10) and can be monocyclic, bicyclic, or tricyclic, provided that at least one of the rings is aromatic. However, when heteroaryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule through an aromatic ring. Heterocyclic groups that may be mentioned include benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), isothiochromanyl, and more preferably acridinyl, benzoimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofurazanyl, benzofuranyl , benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H1,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenodiazolyl (including 2,1,3-benzoselenodiazolyl), benzothienyl, carbazolyl, chromanyl, cynolinyl, furanyl, imidazolyl, imidazo [1,2-a] pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isoxazolyl, naphthyridyl (including 1,6- naphthyridinyl or preferably 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl 50 (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinoline, 8-transhydroxychlorinyl) , tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 1, 3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenethyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl), and so on. Where appropriate, the substituents on heteroaryl groups can be located on any atom of the ring system, including a hetero atom. The point of attachment of the heteroaryl groups can be through any atom of the ring system, including (where appropriate) a hetero atom (such as a nitrogen atom), or an atom in any fused carbocyclic ring that may be present as part of the ring system. The groups

image11

Heteroaryl can also be in the N- or S-oxidized form. Particularly preferred heteroaryl groups include pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, thiadiazolyl, indazolyl, thiifenenyl, indazolyl pyranyl, carbazolyl, acridinyl, quinolinyl, benzoimidazolyl, benzothiazolyl, purinyl, cinnolinyl, and pterdinyl.

Particularly preferred heteroaryl groups include monocyclic heteroaryl groups.

For the avoidance of doubt, when the identity of two or more substituents of a compound of formula I can be the same, the actual identities of the respective substituents are not interdependent in any way. For example, since D may be optionally substituted with one or more R6 groups, then the R6 groups may be the same or different. Similarly, when R6 and R7 are both aryl groups substituted with one or more C16 alkyl groups, the alkyl groups in question may be the same or different. Additionally, when R8, R9, R10, R11, R12, R13, R14, R15a, R15b, R15c, and R15d independently represent R16, then the R16 groups may be the same.

or different.

15 For the avoidance of doubt when an expression such as "A1 to A5" is used herein, those skilled in the art will understand that it means any of A1, A2, A3, A4, and A5 (i.e., some or all, as applicable) inclusively.

All the individual characteristics mentioned in this document (for example the characteristics

20) may be considered in isolation or in combination with any other feature mentioned herein (including the preferred feature) (therefore, preferred features can be considered in conjunction with, or independently of, other preferred features).

Those skilled in the art will appreciate that in some preferred embodiments of the compounds of the invention,

25 some or all of the conditions (a) to (c) above will be redundant (for example, where it is stated that at least one (or both) of the ring containing A1 toA5 and / or ring D, carry a different substituent from hydrogen, then all conditions (a) to (c) above are redundant).

In one embodiment of the invention a compound of formula I is provided wherein: A represents C (= N-W-D) and W represents -C (O) - [CRxRy] p-.

In a further embodiment of the invention a compound of formula I is provided wherein:

A represents C (= N-W-D) and W represents - [CRxRy] m-. In a further embodiment of the invention there is provided a compound of formula I wherein:

B represents C (-NH-W-D) and W represents -C (O) - [CRxRy] p-.

In a further embodiment of the invention there is provided a compound of formula I wherein:

B represents C (-NH-W-D) and W represents - [CRxRy] m-.

Preferred compounds of formula I include those in which at least one of A1 to A5 is not (C-H), and D 45 is substituted with one or more -R6 groups. It is preferable that the ring containing A1 to A5 or ring D is substituted with a substituent other than H.

When it is stated herein that at least one of A1 to A5 is not (C-H), or that ring D is substituted with a substituent other than H, it is meant that:

50 one of A1 to A5 represents N, or preferably one of A1 to A5 represents C (R1), C (R2), C (R3), C (R4) or C (R5) (as appropriate) wherein at minus one of R1, R2, R3, R4 or R5 represents a substituent other than H (that is, at least one of the substituents R1, aR5 representing halogen, -R7, -CF3, -CN, -NO2, C (O) is present R7, -C (O) OR7, -C (O) -N (R7a) R7b, -N (R7a) R7b, -N (R7) 3+, -SR7, -OR7, -NH (O) R7, - SO3R7, aryl or heteroaryl

55 (these same aryl and heteroaryl groups are optionally and independently substituted with one or more groups selected from halogen and R16), or any two of R1 to R5 that are adjacent to each other are linked as defined herein); or ring D represents pyridyl or pyrimidinyl or, preferably, ring D is substituted with one or more R6 groups.

The most preferred compounds of formula I that may be mentioned include those in which: one of A1 to A5 represents N or, preferably, one of A1 to A5 represents C (R1), C (R2), C (R3), C (R4) or C (R5) (as appropriate), wherein at least one of R1, R2, R3, R4, or R5 represents a substituent other than H (e.g., a substituent as defined herein ); and

Ring D represents pyridyl or pyrimidyl or, preferably, Ring D is phenyl substituted with one or more R6 groups.

image12

Preferred compounds of formula I that may be mentioned include those in which:

A represents S.

The most preferred compounds of formula I that may be mentioned include those in which:

B represents S.

Compounds of formula I that may be mentioned include those in which:

each unit - [CRxRy] - can be selected independently of:

(a) a unit in which Rx and Ry are independently selected from H, halogen, C16 alkyl (optionally substituted with one or more heteroatoms); and

15 (b) a unit in which Rx and Ry are linked to form, together with the carbon atom to which they are attached, a 3 to 8 membered non-aromatic ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, this same ring optionally substituted with one or more substituents selected from halogen or C16 alkyl (optionally substituted with one or more halogen atoms), provided that no more than one unit is selected from (b);

(for example, each unit - [CRxRy] - can be selected independently of:

(a) a unit in which Rx and Ry are independently selected from H, halogen, C13 alkyl (optionally substituted with one or more halogen atoms) (eg, at least one of Rx and Ry is H);

(B) a unit in which Rx and Ry are linked to form, together with the carbon atom to which they are attached, a non-aromatic ring selected from cyclobutyl, cyclopentyl, cyclohexyl or, more particularly, cyclopropyl, this same optionally substituted ring with one or more substituents selected from halogen or C16 alkyl (optionally substituted with one or more halogen atoms),

provided that no more than one unit is selected from (b)).

Compounds of formula I that may be mentioned include those in which:

Rx and Ry are linked to form, together with the carbon atom to which they are attached, a non-aromatic ring

3 to 8 membered, optionally containing 1 to 3 heteroatoms selected from O, S, and N; this same ring optionally substituted with one or more substituents selected from halogen and / or C16 alkyl (optionally substituted with one or more halogen atoms).

Additional compounds of formula I that may be mentioned include those in which:

Rx and Ry are linked to form, together with the carbon atom to which they are attached, a cyclobutyl, cyclopentyl, cyclohexyl or, more preferably, cyclopropyl ring; this same ring optionally substituted with one

or more substituents selected from halogen and / or C16 alkyl (optionally substituted with one or more halogen atoms, or more preferably unsubstituted).

Additional compounds of formula I that may be mentioned include those in which:

one unit - [CRxRy] - forms a 3 to 8 membered non-aromatic ring optionally containing 1 to 3 heteroatoms selected from O, S and N; this same ring optionally substituted with one or more substituents selected from halogen or C16 alkyl (optionally substituted with one or more halogen atoms) and, if other - [CRxRy] - units are present, then additional Rx and Ry groups are independently selected H, halogen, C16 alkyl (optionally substituted with one or more halogen atoms)

or aryl (optionally substituted with one or more halogen atoms).

Additional compounds of formula I that may be mentioned include those in which:

a unit - [CRxRy] - is linked to form a cyclobutyl, cyclopentyl, cyclohexyl or, more preferably, cyclopropyl ring; this same ring optionally substituted with one or more substituents selected from halogen or C16 alkyl (optionally substituted with one or more halogen atoms, or more preferably unsubstituted) and, if other - [CRxRy] - units are present, then the Rx groups and additional Ry are independently selected from phenyl (optionally substituted with one or more halogen atoms) or, more preferably, H, halogen, C16 alkyl (optionally substituted with one or more halogen atoms).

65 The above preferences for - [CRxRy] - apply particularly with respect to compounds where the relevant unit is part of the X substituent.

image13

fifteen

25

35

Four. Five

55

Compounds of formula I that may be mentioned include those in which:

Rx and Ry are independently selected from phenyl (optionally substituted with one or more halogen atoms) or, more preferably, H, halogen, C16 alkyl (optionally substituted with one or more halogen atoms).

Additional compounds of formula I that may be mentioned include those in which:

Q represents -S-, preferably -N (CH3) -, -O- or, more preferably, a bond.

Compounds of formula I that may be mentioned include those in which:

when X represents -Q- [CRxRy] n-, then the portion - [CRxRy] n- preferably represents -CRxRy- (for example, -CH2-, -C (-CH2CH2 -) -, that is, -C (cyclopropyl ) -, or -C (H) (aryl) -) or - [CRxRy] 2- (eg -CH2CH2-): when n represents 1, then Rx and Ry independently represent C16 alkyl (eg C13) or, preferably hydrogen or aryl (for example phenyl; optionally substituted with one or more halogen atoms, for example chlorine, thus forming for example a chlorophenyl group), or Rx and Ry are linked together to form a non-aromatic carbocyclic spirocycle of 3 to 6 members (preferably cyclopropyl), said ring preferably unsubstituted; both Rx and Ry, when attached to the same carbon atom, preferably do not represent optionally substituted aryl; when n represents 2, then Rx and Ry independently represent C16 (eg, C13) alkyl or, preferably, hydrogen;

for example, when Q represents a bond, n represents 1 or 2.

More preferred groups that X may represent include -CH2-, -CH2CH2-, -O-CH2CH2-, -N (CH3) -CH2CH2-, S-CH2CH2-, 1,1-cyclopropyl and -C (H) (4 -chlorophenyl) - (that is, it is preferable that X is not a direct bond but represents a group containing at least one bonding atom).

Compounds of formula I that may be mentioned include those in which:

m and p independently represent 0 or 1; when W represents - [CRxRy] m-o - [CRxRy] p, then Rx and Ry independently represent C16 alkyl or, preferably, hydrogen; W represents a direct bond (ie, m represents 0), -CH2-, -C (O) - (ie, p represents 0), or -C (O) CH2-.

The ring containing A1 to A5 may be pyridyl (for example 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl or 6-pyridyl), but is preferably phenyl. Preferably ring D is pyridyl (for example 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl or 6-pyridyl) or, more preferably, phenyl. Each ring can be unsubstituted or substituted with one or two substituents defined herein (with R1 through R6, as appropriate). As indicated herein, in a preferred embodiment of the invention, one of these rings is substituted with at least one substituent other than H as defined herein (with R1 through R6, as appropriate).

The most preferred compounds of formula I include those in which:

A1 to A5 represent C (R1), C (R2), C (R3), C (R4) and C (R5) respectively; D represents phenyl, pyridyl or pyrimidinyl optionally substituted with one or more R6 groups; Rx and Ry, each time used herein, are independently selected from fluorine, preferably H, C16 alkyl (optionally substituted with one or more fluorine atoms), aryl (optionally substituted with one or more fluorine atoms). halogen, eg chlorine), or Rx and Ry are linked to form, together with the carbon atom to which they are attached, a 3 to 8 membered non-aromatic ring (eg, a 3 to 6 membered ring); this same ring optionally substituted with one or more substituents selected from fluorine and / or C16 alkyl (for example, C13, such as C12) (optionally substituted with one or more fluorine atoms), but said 3 to 8 membered ring (for example 3 to 6) is preferably unsubstituted (eg unsubstituted cyclopropyl); R1 to R5 independently represent -CN, -N (R7a) R7b, -N (R7) 3+, -SR7 or, preferably, H, halogen (for example chlorine or fluorine), -R7, -CF3, -C (O ) -N (R7a) R7b, -OR7 or heteroaryl (for example a 5- or 6-membered heteroaryl group preferably containing one to three heteroatoms (preferably nitrogen heteroatoms), and said heteroaryl group is optionally substituted with one or more groups selected from R16 and preferably halogen, eg chlorine); R6 represents, independently on each occasion used herein, -NO2, -NR9R10, -SR11, or, preferably, cyano, halogen, -R8 or -OR8; R7, each time used herein, is selected from H and C16 (for example C13) alkyl (for example methyl), optionally substituted with one or more fluorine atoms (thus forming, for example, a group - CHF2 or, preferably, a group -CF3);

image14

R7a

and R7b are independently selected from H and C16 (eg C13) alkyl (eg methyl), optionally substituted with one or more fluorine atoms (thus forming eg a -CHF2 group or, preferably a -CF3 group); or R7a and R7b are optionally linked to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered aromatic or non-aromatic ring (preferably a non-aromatic ring).

5 or 6 membered aromatic), optionally containing 1 to 3 heteroatoms selected from O, S and N (preferably N heteroatoms); this same ring optionally substituted with one or more substituents selected from fluoro, -R7 and = O; Ra, R8, R9, R10, R11, R12, R13, R14, R15a, R15b, R15c and R15d, each time used herein, independently represent H or R16 (but more preferably Ra and R8 represent R16) ; R16 represents, each time used herein, C16 (C13) alkyl

10 optionally substituted with one or more fluorine atoms (thus forming, for example, a -CHF2 group or, preferably, a -CF3 group).

Additional compounds of formula I that may be mentioned include those in which:

At least one of R1 to R5, when present, represents halogen, -R7, -CF3, -CN, -C (O) R7, -C (O) OR7, -C (O) N (R7a) R7b, -N (R7) 3+, -SR7, -OR7 or -NH (O) R7, or any two of R1 to R5 that are adjacent to each other, are optionally bonded to form, together with two essential benzene ring atoms in the compound of formula I, a 3- to 8-membered aromatic or non-aromatic ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, this same ring optionally substituted with one or more

20 substituents selected from halogen, -R7, -OR7 and = O.

Additional compounds of formula I that may be mentioned include those in which:

at least one of R1 to R5, when present, represents heteroaryl, -OR7, halogen, -CF3, -CN, -C (O) R7,

C (O) -N (R7a) R7b, -C (O) OR7, -N (R7) 3+ or -NH (O) R7, or any two of R1 to R5 that are adjacent to each other are optionally linked to form, together with two essential benzene ring atoms in the compound of formula I, a 3- to 8-membered aromatic or non-aromatic ring selected from 2,3-dihydrobenzo [1,4] dioxynyl or tetrahydroquinolinyl, which may be optionally substituted with one or more halogen atoms.

Additional compounds of formula I that may be mentioned include those in which:

at least one of R1 to R5, when present, represents heteroaryl, -OR7, halogen, -CF3, -CN, -C (O) R7, C (O) OR7, -C (O) -N (R7a) R7b , -N (R7) 3+ or -NH (O) R7. 35 More compounds of formula I that may be mentioned include those in which:

at least one of R1 to R5, when present, represents 4H- [1,2,4] -triazolyl, -OR7 (eg -OCH3, or more preferably -OCHF2 or -OCF3), or, more preferably, -Cl , -F, -CF3, -CN or -C (O) -N (R7a) R7b. 40 More compounds of formula I that may be mentioned include those in which:

at least one of R1 to R5, when present, represents -OR7 or, more preferably, -Cl, -F, -CF3, -CN or C (O) -N (R7a) R7b. Compounds of formula I that may be mentioned include those in which:

R6 independently represents -C (O) NR15aR15b or, more preferably, cyano, -NO2, -Br, -Cl, -F, -R8, -OR8, -NR9R10, -SR11, -C (O) OR13, -C ( O) R14, -S (O) 2NR15cR15d, aryl or heteroaryl (these same aryl and heteroaryl groups are optionally substituted independently with one or more groups selected from halogen and R16), or any two R6 groups that are adjacent to each other are optionally linked to form, together with two essential benzene ring atoms in the compound of formula I, quinoline, tetrahydroquinoline, isoquinoline or tetrahydroisoquinoline, wherein this same additional ring system of the quinoline, tetrahydroquinoline, isoquinoline or tetrahydroisoquinoline portion, is optionally substituted with one or more

55 substituents selected from halogen, -R7, -OR7 and = O.

Additional compounds of formula I that may be mentioned include those in which:

R6 independently represents -C (O) NR15aR15b or, more preferably, -R16 or more preferably cyano,

60 NO2, -Br, -Cl, -F, -OR8, -NR9R10, -SR11, -C (O) OR13, -C (O) R14, -S (O) 2NR15cR15d, aryl or heteroaryl (these same aryl groups and heteroaryl optionally are independently substituted with one or more groups selected from halogen and R16).

More compounds of formula I that may be mentioned include those in which: 65

image15

R6 independently represents -C (O) NR15aR15b, -R16, or, more preferably, -CN, -NO2, -Br, -Cl, -F, -OR8, -NR9R10, -SR11, -C (O) OR13 or - C (O) R14. More compounds of formula I that may be mentioned include those in which:

R6 independently represents -R16 or, more preferably, -CN, -OCF3, -NO2, -Br, -Cl, -F, -OR8, -NR9R10 or -SR11.

More compounds of formula I that may be mentioned include those in which: R6 independently represents -CN, -CF3, -OCF3, -F or, more preferably, -Cl. Compounds of formula I that may be mentioned are those in which: n represents 2 or, more preferably, 1. Additional compounds of formula I that may be mentioned include those in which: m represents 1 or, more preferably, 0; p represents 1 or, more preferably, 0. Additional compounds of formula I that may be mentioned include those in which: A5 represents N or, more preferably, C (Cl) or C (H). Additional compounds of formula I that may be mentioned include those in which: A1 and A5 independently represent N or, more preferably, C (H). Additional compounds of formula I that may be mentioned include those in which: A2 represents C (R2); A1 and A3 to A5 independently represent C (H) or N. More compounds of formula I that may be mentioned include those in which: A2 represents C (R2); R2 represents -CF3; A1 and A3 to A5 independently represent C (H). Additional compounds of formula I that may be mentioned include those in which: A5 represents C (R5); A1 through A4 independently represent C (H) or N. More compounds of formula I that may be mentioned include those in which: A5 represents C (R5); R5 represents -Cl; A1 through A4 independently represent C (H). Compounds of formula I which may be mentioned include those in which: D represents (ortho, para) dichlorophenyl. The compounds of formula I that may be mentioned include those in which:

D represents para-chlorophenyl. The most preferred compounds of formula I include those in the examples described below. Preferred compounds of formula I include:

i) 5- (3,4-dichlorophenyl) imino-4 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazolidin-3-one;

Ii) 5- (3,4-dichlorophenyl) imino-4 - [(4-methoxyphenyl) methyl] -1,2,4-thiadiazolidin-3-one; iii) 4 - [(4-chlorophenyl) methyl] -5- (3,4-dichlorophenyl) imino-1,2,4-thiadiazolidin-3-one;

iv) 5- (3,4-dichlorophenyl) imino-4 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazolidin-3-one; v) 5- (3,4-dichlorophenyl) imino-4 - [(3-fluorophenyl) methyl] -1,2,4-thiadiazolidin-3-one; vi) 5- (3,4-dichlorophenyl) imino-4- [phenyl) methyl] -1,2,4-thiadiazolidin-3-one; vii) 5- (3,4-dichlorophenyl) imino-4-phenethyl-1,2,4-thiadiazolidin-3-one;

Viii) 4- [2 - [(4-chlorophenyl) -methyl-amino] ethyl] -5- (3,4-dichlorophenyl) imino-1,2,4-thiadiazolidin-3-one; ix) 4- [2- (4-chlorophenyl) sulfanylethyl] -5- (3,4-dichlorophenyl) imino-1,2,4-thiadiazolidin-3-one; x) 3 - [[(5- (3,4-dichlorophenyl) imino-3-oxo-1,2,4-thiadiazolidin-4-yl] methyl] -N-methylbenzamide; xi) 5 - [(6-chloro -3-pyridyl) imino] -4 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazolidin-3-one; xii) 4 - [[4 - [(3,4-difluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] amino] benzonitrile; xiii) 4 - [(3,4-difluorophenyl) methyl] -5- [4- (trifluoromethyl) phenyl] imino-1,2,4-thiadiazolidin-3-one; xiv) 4 - [(3,4-difluorophenyl) methyl] -5- [4- (trifluoromethoxy) phenyl] imino-1,2,4-thiadiazolidin-3-one; xv) 3- [5- (3,4-dichlorophenyl) imino-3-oxo-1,2,4-thiadiazolidin-4-yl] methyl] benzonitrile; xvi) 5- (3,4-dichlorophenyl) imino-4 - [[4- (1,2,4-triazol-1-yl) phenyl] methyl] -1,2,4-thiadiazolidin-3-one; xvii) 4- [1- (4-chlorophenyl) cyclopropyl] -5- (4-chlorophenyl) imino-1,2,4-thiadiazolidin-3-one;

Xviii) 5 - [(4-chlorophenyl) methylimino] -4 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazolidin-3-one; N- [3-oxo-2 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazol-5-yl] benzamide; xix) 4-fluoro-N- [3-oxo-2 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazol-5-yl] benzamide; xx) 2- (4-fluorophenyl) -N- [3-oxo-2 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazol-5-yl] acetamide; xxy) 4-chloro-N- [2 - [(3,4-difluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxii) 4-chloro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxiii) 4-chloro-N- [2 - [(4-chlorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxiv) 4-chloro-N- [2- [2- (phenoxy) ethyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxv) 4-chloro-N- [2- [2 - [(4-chlorophenyl) -methyl-amino] ethyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxvi) 4-chloro-N- [2- [2- (4-chlorophenyl) sulfanylethyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide;

Xxvii) 3,4-dichloro-N- [2- [1- (4-fluorophenyl) cyclopropyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxviii) 3,4-dichloro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxix) N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] -4-methoxy-benzamide; xxx) 2,6-dichloro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxxi) 2,4-dichloro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxxii) N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] -4- (trifluoromethoxy) -benzamide; xxxiii) N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] -3,5-bis (trifluoromethyl) -benzamide; xxxiv) 3,4-Difluoro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxxv) 2-chloro-6-fluoro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxxvi) 3,5-Difluoro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide;

Xxxvii) 5- (3,4-dichlorophenyl) imino-4- (2-phenoxyethyl) -1,2,4-thiadiazolidin-3-one; xxxviii) 5- (3,4-dichlorophenylamino) -2- (2-phenoxyethyl) - [1,2,4] thiadiazol-3-one; xxxix) 4-benzohydril-5- (3,4-dichlorophenyl) imino-1,2,4-thiadiazolidin-3-one; xl) 4-chloro-N- [4 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] benzamide; xli) 4-chloro-N- [4 - [(4-chlorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] benzamide; xlii) 4-chloro-N- [3-oxo-4 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazolidin-5-ylidene] benzamide; xliii) N- [4 - [(3-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] -4- (trifluoromethyl) -benzamide;

xliv) N- [4 - [(3-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] -3,5-bis (trifluoromethyl) benzamide; xlv) N- [4 - [(3,4-dichlorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] -3,4-difluoro-benzamide; xlvi) 1,5- (3,4-dichlorophenylamino) -2- (4-methoxybenzyl) - [1,2,4] -thiadiazol-3-one;

Xlvii) 1,5- (3,4-dichlorophenylamino) -2- (4-chlorobenzyl) - [1,2,4] thiadiazol-3-one; xlviii) 1,5- (3,4-dichlorophenylamino) -2- (3,4-difluorobenzyl) - [1,2,4] -thiadiazol-3-one; xlix) 1,5- (3,4-dichlorophenylamino) -2- (3-fluorobenzyl) - [1,2,4] thiadiazol-3-one; l) 1,5- (3,4-dichlorophenylamino) -2- (benzyl) - [1,2,4] thiadiazol-3-one; li) 5- (3,4-dichlorophenylamino) -2-phenethyl- [1,2,4] thiadiazol-3-one; lii) 2- [2 - [(4-chlorophenyl) -methyl-amino] ethyl] -5 - [(3,4-dichlorophenyl) amino] -1,2,4-thiadiazol-3-one; liii) 2- [2- (4-chlorophenyl) sulfanylethyl] -5 - [(3,4-dichlorophenyl) amino] -1,2,4-thiadiazol-3-one; liv) 3 - [[5 - [(4-chlorophenyl) amino] -3-oxo-1,2,4-thiadiazol-2-yl] methyl] -N-methyl-benzamide; lv) 5 - [(6-chloro-3-pyridyl) amino] -2 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazol-3-one; lvi) 2 - [(3,4-difluorophenyl) methyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one;

Lvii) 2 - [(3,4-difluorophenyl) methyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one; lviii) 5 - [(4-chlorophenyl) amino] -2- [1- (4-chlorophenyl) cyclopropyl] -1,2,4-thiadiazol-3-one; lix) 5 - [(3,4-dichlorophenyl) methylamino] -2 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazol-3-one; lx) 3,4-dichloro-N- [4 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] benzamide; lxy) 2 - [(4-methoxyphenyl) methyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one; lxii) 2 - [(4-chlorophenyl) methyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one; lxiii) 2 - [(3-fluorophenyl) methyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one; lxiv) 2- [phenylethyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one; lxv) 2 - [(4-methoxyphenyl) methyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one; lxvi) 2 - [(4-chlorophenyl) methyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one;

65 lxvii) 2 - [(3-fluorophenyl) methyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one; lxviii) 2- [phenylethyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one; and lxix) 4 - [[2 - [(3,4-difluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] amino] benzonitrile.

image16

Compound names were derived using the commercially available software package from Autonom (naming software brand provided as an add-on for use in the Symyx Draw 2.1 (TM) 5 Office Suite available from MDL Information Systems).

Throughout this specification, structures may or may not be presented with chemical names. When there is any doubt regarding the nomenclature, the structure will prevail. When it is possible for a compound to exist as a tautomer, the structure represents one of the possible tautomeric forms, in which

The actual tautomeric forms observed may vary depending on environmental factors, such as solvent, temperature, or pH.

Compounds of formula (I) can be prepared according to techniques that are well known to those skilled in the art, for example as described hereinafter.

According to a further embodiment of the invention, there is provided a process for the preparation of a compound of formula I, which process comprises:

(i) for compounds of formula I in which A represents S, cyclization of a compound of formula IIa:

W image17

image18 NH

S

image19 NH

OR image20 NH

X

image21

image22

image23

IIa

D

2

image24 image25 TO

TO

5

TO

4

3

image26

wherein A1 through A5 and X are as defined hereinbefore, with a compound of formula IV: L2-W1-D IV

wherein L2 represents a suitable leaving group, such as halogen (eg, chlorine), W1 represents [CRxRy] m- where m represents 1, and D is as defined hereinbefore, under conditions of reaction known to those skilled in the art, for example in the presence of a suitable base (for example, NaH, NaOH, triethylamine, pyridine, another suitable base mentioned in the step step of the process, or mixtures thereof) and a solvent ( eg pyridine (which can serve as the base and solvent), DMF or dichloromethane (eg also in the presence of water and optionally a phase transfer catalyst)), eg at room temperature eg as described Hurst, DT; Stacey,

50 A. D., Netercleft, M., Rahim, A., Harnden, M. R. Aust. J. Chem. 1998, 41, 1221;

(iii) for compounds of formula I in which A represents S, W represents - [CRxRy] m- and m represents 0, the reaction of a compound of formula III as defined above, with a compound of formula V:

L3-D V

wherein L3 is a suitable leaving group (eg halogen) and D is as defined hereinbefore, under reaction conditions known to those skilled in the art, eg in

5 presence of a suitable base (for example, a tributyltin amine or cyclohexylamine and lithium bis (trimethylsilyl) amide), a suitable catalyst (for example, PdCl2 (P (o-toluyl) 3) 2), a solvent suitable (eg toluene) and at a suitable temperature (eg room temperature to 105 ° C), eg as described by Harwig et al. J. Am. Chem. Soc. (1994), 116, 5969-5970; Buchwald et al. J. Am. Chem. Soc. (1994), 116, 7901-7902; and Buchwald et al. Org. Process Res. Dev. (2006) 10 (4), 762-769;

10

(iv) for compounds of formula I in which A represents S, W represents -C (O) - [CRxRy] p-, the reaction of a compound of formula III as defined above, with a compound of the formula SAW:

L4-W2-D VI

Wherein L4 is a suitable leaving group (eg halogen) or -OH, W2 represents -C (O) - [CRxRy] p-, and D is as defined hereinbefore, when L4 represents a suitable leaving group, under reaction conditions known to those skilled in the art, for example in an appropriate solvent (for example, toluene, xylene, DCM, chloroform), optionally in the presence of a base (for

20 for example pyridine, Hunig's base, triethylamine), and at reduced to elevated temperatures (for example, 0 ° C to 140 ° C), or when L4 represents OH, under standard coupling reaction conditions, for example in the presence of a reagent suitable coupling agent (e.g. 1,1'-carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide, 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide (or the hydrochloride thereof), N, N'-disuccinimidyl carbonate , benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate, 2-hexafluorophosphate

25 (1H-Benzotriazol-1-yl) -1,1,3,3-tetramethyluronium, benzotriazol-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate, bromo-tris-pyrrolidinophosphonium hexafluorophosphate, 2- (1H-benzotriazole tetrafluorocarbonate) yl) -1,1,3,3-tetramethyluronium), or 1-cyclohexylcarbodiimide-3-propyloxymethyl polystyrene, optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinepyridine, pyridine, triethylamine , tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1.8

30 diazabicyclo [5,4,0] undec-7-ene, sodium hydroxide, N-ethyldiisopropylamine, N- (methylpolystyrene) -4 (methylamino) pyridine, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide , potassium tert-butoxide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, or mixtures thereof), and an appropriate solvent (for example tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile or dimethylformamide), and at reduced to elevated temperatures (eg, 0 ° C to 140 ° C);

35

(v) for compounds of formula I where A represents S, and Q is an -O- or -S- bond, the reaction of a compound of formula VII:

D

VII

OR

Wherein W and D are as defined hereinbefore, with a compound of the formula

VIII:

x and VIII

Q [CR R] n L5

4

Wherein A1 through A5, Rx and Ry are as defined hereinbefore, L5 is a suitable leaving group (eg, bromine, chlorine, iodine) and Q is an -O- or -S- bond, under reaction conditions known to those skilled in the art, for example in the presence of a suitable base (for example, NaH, NaOH, triethylamine, pyridine), and in a solvent (for example pyridine (which can serve as the base and the solvent),

50 DMF or dichloromethane (for example also in the presence of water and optionally a phase transfer catalyst)), for example at room temperature, for example as described by Hurst, D. T .; Stacey,

A. D., Netercleft, M., Rahim, A., Harnden, M. R., Aust. J. Chem. 1998, 41, 1221;

(vi) for compounds of formula I in which A represents S and W is - [CRxRy] m-, the reaction of a compound of formula IX:

image27

image28

image29

image30 S image31 image32 A image33 image34 X LA1 N 6

2

IXN

A A

A3

4 O

wherein L6 represents a suitable leaving group (eg halogen) and A1 toA5 and X are as defined hereinbefore, with a compound of formula X: H2N-W-D X

wherein W and D1 to D5 are as defined hereinbefore, under reaction conditions known to those skilled in the art, for example those described by Keilen et al. (Acta Chemica

10 Scandinavica 1988, B 42, 363-366), for example in a suitable solvent (for example, chloroform, methylene chloride), in the presence of a suitable base (for example, a Hunig's base, thietrilamine) and at a suitable temperature (for example, from room temperature to 150 ° C, such as less than <100 ° C); and

(vii) for compounds of formula I in which B represents S, cyclization of a compound of formula IIa:

image35 OR

image36 image37 TO image38 X image39 image40 IIb

N NH

TO

2

2

AA

5 A 3 S NH

4

W

D

Compounds of formula IIa can be prepared by reacting a compound of formula XI:

image41 OR

image42 image43 TO image44 1 image45 X image46

AN NH

2

H 2 XI

A A

A3 4

Wherein A1 through A5 and X are as defined hereinbefore, with a compound of the formula

XII:

XII

2

3. 4

Wherein W and D1 to D5 are as defined hereinbefore, under reaction conditions known to those skilled in the art, for example in a suitable solvent (for example, acetone, dimethylformamide, or 20% dimethylformamide in acetonitrile), at a suitable temperature (e.g. -10 ° C to

30 50 ° C) and in the presence of a base, as described for example in Castro et al. (Bioorganic. Med. Chem. 2008, 16, 495-510) or Kaugars et al. (J. Org. Chem. 1979, 44 (22), 3840-3843). Alternatively, a compound of formula I can be formed directly by treating any product so formed under reaction conditions such as those described above (eg, step (i) of the above process).

The compounds of formula IIb can be prepared by reacting a compound of formula XI described hereinabove, with a compound of formula XII under reaction conditions known to the person skilled in the art, for example in a suitable solvent (for e.g. acetone, dimethylformamide), at a temperature

image47

image48

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

55

(eg, -10 ° C to 50 ° C), and in the presence of a suitable base, eg n-butyllithium), as described eg in Castro et al. (Bioorganic. Med. Chem. 2008, 16, 495-510) or Kaugars et al. (J. Org. Chem. 1979, 44 (22), 3840-3843). Alternatively, a compound of formula I can be formed directly by treating any product so formed under reaction conditions such as those described hereinbefore (eg, step (vii) of the above process).

Alternatively, compounds of formula IIb can be formed by the selective N-alkylation of N- (3-oxo-1,2,4-thiadiazolidin-5-ylidene) amide derivatives, as described by Castro et al. (Bioorganic. Med. Chem. 2008, 16, 495-510).

Compounds of formula IX can be prepared by reacting a compound of formula III with NaNO2 and a suitable halogen source (for example, hydrochloric acid) under reaction conditions known to those skilled in the art, for example such as described. by Foroumadi et al. (1999) Arzneim. Forsch. 49, 10351038, or Foroumadi et al. (2005) Arch. Pharm. Chem. Life Sci. 338, 112-116, for example in the presence of a suitable metal (for example powdered copper).

Compounds of formula XI can be prepared by analogy with the methods described by Xu et al. (Tetrahedron Lett. 1998, 39, 1107-1110) and Katritsky et al. (ARKIVOC (Archive for Organic Chemistry) 2003 (viii) 8-14).

For compounds of formula XII where W represents -C (O) -, the reaction of a compound of formula XIII:

image49 O XIII

DHO

image50 D2

D image51 D

3. 4

5 D

or the corresponding acyl halide (for example, acyl chloride), or derivatives thereof where D1 to D5 are as defined hereinbefore, with a thiocyanate (for example, an alkali metal thiocyanate, such as potassium thiocyanate), under reaction conditions known to those skilled in the art, for example in the presence of a suitable solvent (such as acetone), as described by Cho et al, J. Heterocyclic Chem. 1991, 28, 1645- 1649).

Compounds of formulas III, IV, V, VI, VII, VIII, X and XIII are commercially available, are known from the literature, or can be obtained by analogy with the processes described herein (or the processes described in references contained herein), or by means of conventional synthetic procedures, according to standard techniques, starting from available starting materials and using the appropriate reagents and reaction conditions.

Substituents such as R2, R3 and R4 in the final compounds of formula I (or precursors thereof and other relevant intermediates) can be modified one or more times after or during the processes described above, by means of methods that are well known. for experts in the field. Examples of such methods include substitutions, reductions (eg, carbonyl bond reductions in the presence of suitable reducing agents and, if necessary, chemoselectives, such as LiBH4 or NaBH4), oxidations, alkylations, acylations, hydrolysis, esterifications, and etherifications. The parent groups can be changed to a different group, or to the groups defined in formula I at any time during the reaction sequence.

Compounds of formula I can be isolated from their reaction mixtures using conventional techniques.

Those skilled in the art will appreciate that in the processes described above and those described below, it may be necessary to protect the functional groups of the intermediates with protecting groups.

Protection and deprotection of functional groups can occur before or after a reaction in the schemes mentioned above.

Protecting groups can be removed according to techniques that are well known to those of skill in the art, and as described hereinafter. For example, the protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques.

The type of chemistry involved will dictate the need and type of protecting groups, as well as the sequence to perform the synthesis.

The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by J W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1999).

As used herein, the term "functional groups", in the case of unprotected functional groups, means a hydroxy-, thiolo-, amino-, carboxylic acid function and, in the case of protected functional groups, alkoxy lower, N-, O-, S-acetyl, carboxylic acid ester.

Medical and pharmaceutical uses

The compounds of formula I are indicated as medicaments. According to a further embodiment of the invention, there is provided a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament. Conveniently, the compounds of formula I can be AMPK agonists, that is, they can activate AMPK. By "activating AMPK", it is meant that the degree of phosphorylation state

The steady state of the Thr-172 portion of the AMPK-α subunit is increased compared to the degree of steady-state phosphorylation in the absence of the agonist. Alternatively or additionally, it means that there is a higher degree of steady state phosphorylation of any other protein ahead of AMPK, such as acetyl-CoA carboxylase (ACC).

The compounds of formula I can be activators of AMPK; therefore, they may be useful in treating diseases, such as those described herein, especially cancer.

Compounds of formula I can reduce the rate of cell proliferation when tested in an assay using a human breast cancer cell line (eg, MDA-MB-231). Therefore,

Compounds may have a beneficial inhibitory effect on the ability of tumors of this type and cancer in general to survive. Compounds of formula I can also reduce the rate of cell proliferation when tested in other cancer cell lines (eg, any p53 mutant or p53 null cell lines), such as, but not limited to, MCF-7, PC -3, Jurkat, SK-OV-3, HL60, MV4-11, HT-29, K562, MDA-MB-231, HCT116wt, A-549, DU-145, LOVO, HCT-116 and PANC-1, independently p53 status.

The compounds of formula I are therefore indicated for the inhibition of cell proliferation. Therefore, the compounds of formula I are indicated for use in the treatment of cancer.

According to a further embodiment of the invention, the use of a compound of formula I, or a

Pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of cancer.

The compounds of formula I may be useful in the treatment of primary and metastatic cancer.

40 It will be understood by those skilled in the art that the term "cancer" includes one or more diseases of the class of disorders that are characterized by the uncontrolled division of cells and the ability of these cells to invade other tissues, either by growth direct into adjacent tissue by invasion, proliferation, or by implantation to distant sites by metastasis.

In a preferred embodiment, the compounds of formula I are capable of inhibiting the proliferation of cancer cells. By "proliferation" is included an increase in the number or size of cancer cells.

Alternatively or preferably, in addition, the compounds of formula I are capable of inhibiting cancer cell metastasis.

By "metastasis" is meant the movement or migration (eg, invasiveness) of cancer cells from a primary tumor site in the body of a subject, to one or more other areas within the subject's body (in which the cells can later form secondary tumors). Therefore, in one embodiment the invention provides compounds and methods for inhibiting, in whole or in part, the formation of secondary tumors in a subject with

55 cancer. It will be appreciated by those skilled in the art that the effect of a compound of formula I on "metastasis" is distinct from any effect that such compound may or may not have on cancer cell proliferation.

Conveniently, the compounds of formula I may be capable of selectively inhibiting the proliferation or metastasis of cancer cells.

By "selectively" it is meant that the combination product inhibits the proliferation and / or metastasis of cancer cells to a greater extent than it modulates the function (eg, proliferation) of non-cancer cells. Preferably, the compound only inhibits the proliferation or metastasis of cells.

65 cancerous.

Image52

The compounds of formula I may be suitable for use in the treatment of any type of cancer, including all tumors (non-solid and preferably solid tumors, such as carcinoma, adenoma, adenocarcinoma, cancer of the blood, regardless of the organ ). For example, cancer cells can be selected from the group consisting of cancer cells of the breast, bile duct, brain, colon, stomach, reproductive organs, thyroid, hematopoietic system, lung and respiratory tract, skin, gallbladder, liver, nasopharynx, nerve cells, kidney, prostate, lymphatic glands and gastrointestinal tract. Preferably, the cancer is selected from the group of colon cancer (including colorectal adenomas), breast cancer (for example, postmenopausal breast cancer), endometrial cancer, cancer of the hematopoietic system (for example, leukemia, lymphoma, etc. .), thyroid cancer, kidney cancer, adenocarcinoma

10 esophageal cancer, ovarian cancer, prostate cancer, pancreatic cancer, gallbladder cancer, liver cancer, and cervical cancer. Most preferably, the cancer is selected from the group of colon, prostate and, particularly, breast cancer. When the cancer is a non-solid tumor, it is preferably a hematopoietic tumor, such as leukemia (eg acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL).

Preferably, the cancer cells are breast cancer cells.

According to a further embodiment of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating cancer, such method

20 comprises administering an effective amount of such compound, or pharmaceutically acceptable salt or solvate thereof, to a patient in need of such treatment.

The compounds of formula I can also be used in the treatment of a disorder or condition alleviated by AMPK activation.

Compounds of formula I may be suitable for use in treating side effects caused by cancer (eg cachexia).

According to a further embodiment of the invention, the use of a compound of formula I, or a

A pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a disorder or condition alleviated by AMPK activation.

Those skilled in the art will understand that the term "disorder or condition alleviated by AMPK activation" also includes, in addition to cancer, diabetes, hyperinsulinemia, and associated conditions, a condition / disorder.

35 in which fibrosis plays a role, sexual dysfunction, osteoporosis, and neurodegenerative diseases.

Therefore, the compounds of formula I may also be indicated for use in the treatment of a disorder or condition caused by hyperinsulinemia, associated with hyperinsulinemia, or contributed to by hyperinsulinemia.

Those skilled in the art will understand that the term "disorder or condition caused by hyperinsulinemia, associated with hyperinsulinemia, or to which hyperinsulinemia contributes", or "treatment of hyperinsulinemia or an associated condition" includes hyperinsulinemia and associated conditions such as type 2 diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, hyperinsulinism in childhood,

45 hypercholesterolemia, high blood pressure, obesity, fatty liver conditions, diabetic nephropathy, diabetic nephropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular conditions such as stroke, systemic lupus erythematosus, neurodegenerative diseases, such as Alzheimer's disease, and syndrome polycystic ovary. Other diseases include progressive kidney disease, such as chronic kidney failure. Preferred disorders include hyperinsulinemia and in particular type 2 diabetes.

Some compounds of formula I may also have the additional advantage of showing partial agonist activity and therefore may be useful in conditions such as late type 2 diabetes, where stimulation of insulin production is required. By "agonist activity" we include direct and indirect acting agonists.

According to a further embodiment of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating a disorder or condition alleviated by AMPK activation, comprising administering an effective amount of such a compound, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need of such treatment. An effective amount can be determined by a physician and will be determined for a specific patient by

60 evaluation of the patient's clinical parameters, including, but not limited to, stage of disease, age, gender, and histology.

The compounds of formula I, in this way, may also be useful in the treatment of a condition / disorder in which fibrosis plays a role. Compounds of formula I may also be useful in the

65 treatment of sexual dysfunction (for example, treatment of erectile dysfunction).

A condition / disorder in which fibrosis plays a role includes (but is not limited to) wound healing, keloids, scleroderma, pulmonary fibrosis (including idiopathic pulmonary fibrosis), nephrogenic systemic fibrosis and cardiovascular fibrosis (including endomyocardial fibrosis), sclerosis systemic, cirrhosis of the liver, macular degeneration of the eye, retinal and vitreous retinopathy, Crohn's disease / inflammatory bowel disease,

5 formation of postsurgical scar tissue, fibrosis induced by radiation and chemotherapeutic drugs, and cardiovascular fibrosis.

Therefore, the compounds of formula I can also be used in the treatment of osteoporosis.

Therefore, the compounds of formula I can also be used in the treatment of inflammation.

Therefore, the compounds of formula I can also be used in the treatment of sexual dysfunction.

Therefore, the compounds of formula I can also be used in the treatment of heart failure.

Therefore, the compounds of formula I can also be used in the treatment of neurodegenerative diseases (for example Alzheimer's disease, Parkinson's disease and Huntington's disease, amyotrophic lateral sclerosis, polyglutamine disorders, such as muscular atrophy spinal and bulbar (SBMA), dentato-rubric-pallidolusian atrophy (DRPLA), and various spinocerebellar ataxias (SCA)).

For the avoidance of doubt, in the context of the present invention, the terms or expressions "treatment", "therapy" and "method of therapy" include therapeutic or palliative treatment of patients in need thereof, as well as prophylactic treatment. and / or the diagnosis of patients who are susceptible to relevant disease states.

25 "Patients" includes mammalian (including human) patients.

The term "effective amount" refers to an amount of a compound that confers a therapeutic effect on the treated patient (eg, sufficient to treat or prevent disease). The effect can be objective (i.e.

30 measurable by means of some test or marker), or subjective (that is, the subject gives an indication or feels an effect).

According to the invention, the compounds of formula I can be administered alone, but preferably they are administered in the form of a pharmaceutical preparation comprising the compound in a dosage form.

Pharmaceutically acceptable, orally, intravenously, intramuscularly, cutaneous, subcutaneous, transmucosal (for example sublingual or buccal route), rectal, transdermal, nasal, pulmonary (for example, tracheal or bronchial route), topical,

or by any other parenteral route. Preferred modes of delivery include oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal delivery.

The compounds of formula I will generally be administered as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due consideration of the desired route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers must be chemically inert to the active compounds and have no harmful side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations can be found, for example,

45 in "Remington The Science and Practice of Pharmacy", 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). For parenteral administration an aqueous solution acceptable for parenteral use can be used which is pyrogen-free and has the required pH, isotonicity and stability. Suitable solutions will be well known to the person skilled in the art; numerous methods being described in the literature. A brief review of drug delivery methods can also be found, for example, in Langer, Science 249, 1527

50 (1990).

Otherwise, the person skilled in the art can prepare suitable formulations in a non-inventive manner using routine techniques, or in accordance with standard or accepted pharmaceutical practice.

Another aspect of the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with a pharmaceutically acceptable excipient, such as an adjuvant, diluent, or carrier. .

The amount of compound of formula I in the formulation will depend on the severity of the condition and the patient.

60 treated, as well as the compound or compounds used, but can be determined in a non-inventive way by the person skilled in the art.

Depending on the disorder and the patient treated, and the route of administration, the compounds of formula I can be administered to a patient in need thereof at varying therapeutically effective doses.

65

5

fifteen

25

35

Four. Five

55

65

However, the dose administered to a mammal, particularly a human, in the context of the present invention, should be sufficient to effect a therapeutic response in the mammal within a reasonable time frame. The person skilled in the art will recognize that the selection of the exact dose and the most appropriate composition and delivery regimen will also be affected, among other things, by the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the patient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient treated, and the stage / severity of the disease.

Administration can be continuous or intermittent (eg by bolus injection). The dose can also be determined by the schedule and frequency of administration. In the case of oral or parenteral administration, the dose can range from about 0.01 mg to about 1000 mg per day of a compound of formula I (or if used, a corresponding amount of a pharmaceutically acceptable salt or prodrug thereof) .

In either case, the physician or other expert will be able to routinely determine the actual dosage that will be most suitable for an individual patient. The doses mentioned above are exemplary of the average case; of course, there may be individual instances where higher or lower dose ranges are warranted, and are within the scope of this invention.

The compounds of formula I can be used or administered in combination with one or more additional drugs useful in the treatment of cancer, in combination therapy.

According to a further embodiment of the invention, a combination product is provided comprising:

(TO)

a compound of formula I; and

(B)

another therapeutic agent useful in the treatment of cancer;

wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Other therapeutic agents useful in the treatment of cancer include standard cancer therapies, such as cytostatic therapy, irradiation, and photodynamic therapy, among others known to the physician.

It is preferred that the other therapeutic agent is a cytostatic agent (such as a taxane (eg docetaxel and particularly paclitaxel), or preferably a platinum (eg cisplatin and carboplatin), or an anthracycline (eg doxorubicin)), or an angiogenesis inhibitor, or a salt or solvate of any of these. However, the other therapeutic agent can also be selected from:

(i)

tamoxifen or a pharmaceutically acceptable salt, solvate or pharmaceutically functional derivative thereof;

(ii)

an aromatase inhibitor (ie, a compound that blocks the production of estrogen from adrenal androgens via the aromatase pathway in peripheral tissues), or a pharmaceutically acceptable salt, solvate, or pharmaceutically functional derivative thereof; Preferred Al's include anastrozole, letrozole, and exemastane;

(iii) trastuzumab (Herceptin), or another antibody that is useful in treating cancer, such as bevacizumab, cetuximab, or panitumumab;

(iv)

a tyrosine kinase inhibitor (i.e., a compound that blocks (or is capable of blocking), to a measurable degree, the autophosphorylation of tyrosine residues, thereby preventing the activation of intracellular signaling pathways in tumor cells) , or a pharmaceutically acceptable salt, solvate or pharmaceutically functional derivative thereof; Preferred TKIs include inhibitors of the vascular endothelial growth factor (VEGF) family, and / or the HER family of TKs, such as HER-1 / human epidermal growth factor (EGFR; erbB1), HER3 (erbB3), HER4 (erbB4), and more particularly HER2 (erbB2); thus, preferred TKIs include imatinib, gefitinib, erlotinib, canertinib, sunitinib, zactyme, vatalanib, sorafenib, leflunomide, and particularly lapatinib;

(v)

a glitazone, such as troglitazone, pioglitazone, and rosiglitazone, or a pharmaceutically acceptable salt, solvate, or pharmaceutically functional derivative thereof;

(saw)

a biguanide, such as phenformin, buformin or more preferably metformin, or a pharmaceutically acceptable salt, solvate or pharmaceutically functional derivative thereof;

(vii) a statin, such as fluvastatin, sinvastatin, rosuvastatin, pravastatin, atorvastatin and particularly lovastatin, or a pharmaceutically acceptable salt, solvate or pharmaceutically functional derivative thereof;

(viii) an inhibitor of mammalian rapamycin target activity (mTOR), such as rapamycin, or a pharmaceutically acceptable salt, solvate, or pharmaceutically functional derivative thereof;

(ix)

an oligomycin, such as oligomycin A, oligomycin B, oligomycin C, oligomycin D (rutamycin A), oligomycin E, oligomycin F, rutamycin B, 44-homooligomycin A and 44-homooligomycin B, or a pharmaceutically acceptable salt, solvate or pharmaceutically derivative functional thereof;

(x)

AICAR (aminoimidazole carboxamide ribonucleotide), or a pharmaceutically acceptable salt, solvate or

pharmaceutically functional derivative thereof;

(xi)

a peroxisome proliferator activated receptor (PPAR) agonist (which also includes thiazolidinediones), or a pharmaceutically acceptable salt, solvate, or pharmaceutically functional derivative thereof;

image53

5 (xii) A-769662, or a pharmaceutically acceptable salt, solvate or pharmaceutically functional derivative thereof;

(xiii) D942 (5- (3- (4- (2- (4-fluorophenyl) ethoxy) -phenyl) propyl) furan-2-carboxylic acid), or a pharmaceutically acceptable salt, solvate or pharmaceutically functional derivative thereof;

(xiv) AM251 (a CB1 receptor antagonist), or a pharmaceutically acceptable salt, solvate or pharmaceutically functional derivative thereof;

(xv) a SIRT1 activator, such as resveratrol and SRT-1720 (N- [2- [3- (piperazin-1-ylmethyl) imidazo [2,1-b] [1,3] thiazol6-yl] phenyl] quinoxaline-2-carboxamide), or a pharmaceutically acceptable salt, solvate or pharmaceutically functional derivative thereof; me

(xvi) salidroside, or a pharmaceutically acceptable salt, solvate or pharmaceutically functional derivative thereof.

By "agonist" we include direct and indirect acting agonists.

It has recently been suggested in the literature (see for example Mol. Cancer Ther., 5, 430 (2006), Cancer Res., 20 66, 10269 (2006), and Int. J. Cancer, 118, 773 (2006)) that the aforementioned classes (v) to (vii) of compounds can be used in the treatment of cancer as described herein.

When the other therapeutic agent is (particularly) of category (i) or (ii) above, the combination products according to embodiments of the invention are particularly useful in the treatment of ER-positive cancer and / or cancer of early stage breast, for example in adjuvant therapy (i.e. reducing the risk of cancer that comes back after surgery), in neoadjuvant therapy (before surgery, to shrink a large breast cancer in such a way that a lumpectomy), in the management of breast cancer that has returned after initial treatment, or in the management of breast cancer that cannot be removed when first diagnosed. Such combination products according to embodiments of the invention

30 are also particularly useful in treating patients at high risk for breast cancer.

When the other therapeutic agent is (particularly) of category (iii) or (iv) above, the combination products according to embodiments of the invention are particularly useful in the treatment of HER2 positive cancer.

The pharmaceutically acceptable salts, solvates or pharmaceutically functional derivatives of any of the compounds listed in categories (i), (ii) and (iv) to (xvi) above are as described hereinbefore. In particular, when the other therapeutic agent is tamoxifen, preferred pharmaceutically acceptable salts include those of citric acid; when the other therapeutic agent is imatinib, the pharmaceutically acceptable salts

Preferred include the mesylate salts; and when the other therapeutic agent is sunitinib, preferred pharmaceutically acceptable salts include the maleate salts.

Combination products as described herein provide for the administration of a compound of formula I in conjunction with the other therapeutic agent, and therefore can be presented as

45 separate formulations, wherein at least one of the formulations comprises the compound of formula I, and at least one comprises the other therapeutic agent, or may be presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation including the compound of formula I and the other therapeutic agent).

50 Therefore, it is further provided:

(1) pharmaceutical formulations that include a compound of formula I; another therapeutic agent useful in the treatment of cancer; and a pharmaceutically acceptable adjuvant, diluent, or carrier; and

55 (2) parts kits comprising the components:

(a) a pharmaceutical formulation that includes a compound of formula I in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation that includes another therapeutic agent useful in the treatment of cancer, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier;

said components (a) and (b) each provided in a form suitable for the administration of one in conjunction with the other.

Components (a) and (b) of the part kits described herein can be administered simultaneously or sequentially.

5

fifteen

25

35

Four. Five

55

65

According to a further embodiment of the invention, there is provided a method of preparing a kit of parts as defined above, the method comprising associating component (a), as defined above, with component (b) as defined above. defined above, thus making the two components suitable for the administration of one in conjunction with the other.

By "associating" the two components with each other, it is meant that components (a) and (b) of the kit of parts can be:

(i)

provided as separate formulations (that is, independently of each other), which are subsequently used together, one in conjunction with one another in combination therapy; or

(ii)

packaged and presented together as separate components of a "combination pack" to be used in conjunction with one another in combination therapy.

Therefore, a kit of parts is further provided comprising:

(I)

one of components (a) and (b) as defined herein; With

(II)

instructions for using that component in conjunction with the other two components.

The kits of parts described herein may comprise more than one formulation that includes an appropriate amount / dose of the compound of Formula I, or more than one formulation that includes an appropriate amount / dose of the other therapeutic agent, to provide for repeated administration. If more than one formulation (comprising any active compound) is present, such formulations may be the same, or they may be different, depending on the dose of each compound, chemical composition, or physical form.

With respect to kits of parts as described herein, by "administration in conjunction with" is included the respective formulations comprising the compound of formula I and the other therapeutic agent administered sequentially, separately, or simultaneously during the course. treatment of the relevant condition.

Therefore, with respect to the combination product according to embodiments of the invention, the term "administration in conjunction with" includes that the two components of the combination product (the compound of formula I and the other therapeutic agent) are administered (optionally repeatedly), either together, or at a time close enough to allow a beneficial effect for the patient, which is greater during the course of treatment of the relevant condition than when a formulation comprising a compound of formula is administered I, or a formulation comprising the other therapeutic agent administered alone (optionally repeatedly), in the absence of the other component, during the same course of treatment. The determination of whether a combination provides a greater beneficial effect with respect to a particular condition, and during the course of treatment thereof, will depend on the condition treated or prevented, but can be performed routinely by one of ordinary skill in the art.

Furthermore, in the context of a kit of parts according to embodiments of the invention, the term "in conjunction with" includes that one or the other of the two formulations can be administered (optionally repeatedly) before, after, or at the same time as the administration of the other component. When used in this context, the terms "administered simultaneously" and "administered at the same time" include administering individual doses of the compound of Formula I and the other therapeutic agent over the course of 48 hours (eg, 24 hours) relative to each other. other.

The compounds / combinations / methods / uses described herein may have the advantage that, in treating the conditions described herein, they may be more convenient for the physician and / or patient, they may be more effective, less toxic, have higher selectivity, have a broader scale of activity, be more potent, produce fewer side effects, or may have other useful pharmacological properties, over compositions, combinations, methods (treatments) or similar uses known in the prior art for the treatment of conditions or others, for example on the compounds disclosed in international patent applications WO 2007/010273 and WO 2007/010281.

Furthermore, such advantages may stem from the compounds of formula I being AMPK activators (for example, especially where it is said that the compounds described herein may have higher selectivity, and may produce fewer side effects, for example effects gastrointestinal secondary).

Preferred non-limiting examples incorporating some aspects of the invention will now be described with reference to the following figures:

Figure 1, showing the effect of the compound of Example 1 or the compound of Example 2c on phosphorylation of AMPK. After starvation of PC3 cells in serum-free medium for 24 hours, 0.3, 0.6, 1.2 and 2.5 µM of the compound of Example 1 or the compound of Example 2c were added, and incubated for 4 additional hours. The figure provides representative immunoblots of AMPK phosphorylation with the compound of Example 1 or the compound of Example 2c. The compound of Example 1 and the compound of Example 2c stimulate phosphorylation of AMPK in PC3 cells.

image54

5 Figure 2, which shows the effect of the compounds selected from the examples on AMPK phosphorylation compared to total AMPK levels, and on the phosphorylation of acetyl coenzyme A (acetyl-CoA) carboxylase (an AMPK substrate) . After starvation of PC3 cells in serum-free medium for 16 hours, 1 and 5 µM of the selected compounds were added and incubated for an additional 4 hours. The figure provides representative immunblots of total AMPK (Pan-AMPK) level and AMPK level and the

10 Phosphorylation of acetyl-CoA carboxylase with the compounds selected from the examples. Compounds selected from the examples stimulate phosphorylation of AMPK in PC3 cells and induce phosphorylation of acetyl-CoA carboxylase.

Figure 3, which shows that the compounds of Example 1 and Example 2c can reduce the dephosphorylation of

15 AMPK mediated by PP2C-α1. Compounds were tested at concentrations of 2.5, 5 and 10 µM (as depicted in the figure).

Examples

The invention is illustrated by means of the following examples, in which the following abbreviations may be used:

BrdU 5-bromo-2-deoxyuridine nBuLi N-butyllithium

25 DCM dichloromethane DMF dimethylformamide DMSO dimethyl sulfoxide ES electrospray Et2O diethyl ether

30 EtOAc ethyl acetate EtOH ethanol LC liquid chromatography MeOH methanol MS mass spectrometry

35 MTBE methyl tert-butyl ether NMR nuclear magnetic resonance THF tetrahydrofuran

When preparative routes are not included, the relevant intermediary is commercially available (eg from Chemical Diversity, San Diego, CA, USA, or other commercially available vendors).

General procedures

LC-MS was made on a Sciex API 150 LC / ES-MS equipped with an ACE 3 C8 column (30 x 3.0 mm) using a flow

45 of 1 ml / min. Two gradient systems of acetonitrile in water (with 0.1% TFA) were used for elution: A) 5100% in 10 minutes, then 2 minutes 100% isocratic, or B) 90-100% in 2 minutes, then 2 minutes 100% isocratic. A direct entry ES-EM was also done on a Bruker Esquire CL / ES-EM apparatus. 1H nuclear magnetic resonance was recorded on a Bruker Avance DRX 400 spectrometer at 400.1 MHz, using residual solvent as an internal standard.

50 General procedure for the synthesis of benzoyl isothiocyanates from benzoyl chlorides

To a mixture of benzoyl chloride (5 mmol) and tributylamine bromide (0.15 mmol) in toluene (10 ml) was added potassium isothiocyanate (13 mmol) in water (10 ml) at room temperature. The mixture was stirred at

55 room temperature for 18 hours. The phases were separated and the aqueous phase was extracted with toluene (2X20 ml). The combined organic phase was dried over MgSO4, filtered through a small plug of silica gel, and evaporated to yield benzoyl isothiocyanate in high purity according to 1H NMR. The material was used in the next step without further purification.

60

Example 1

5- (3,4-Dichlorophenyl) imino-4 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazolidin-3-one

5

(i) 1 [(3,4-Dichlorophenyl) carbamothioyl] 1 [[3 (trifluoromethyl) phenyl] methyl] urea

To a solution of 3-trifluoromethylbenzylurea (218 mg, 1 mmol) in dry THF (2 ml) under nitrogen, was added dropwise

10 drop n-BuLi (2.5 M in hexane, 0.4 ml). The mixture was stirred at rt. for 30 min and then 3,4-dichlorophenyl isothiocyanate (204 mg, 1 mmol) in dry THF (2 ml) was added dropwise. HPLC analysis after 5 min revealed the complete reaction to the expected product. Saturated NaHCO3 solution (5 ml) and Et2O (15 ml) were added and the phases were separated. The aqueous phase was extracted with Et2O (2x15 ml). The combined organic phase was washed with brine (5 ml) and dried over MgSO4. Concentration in vacuo gave 412 mg of a colored oil

15 yellow. Purification by flash chromatography (silica, 20-30% EtOAc in n-hexane) gave 193 mg (46%) of pure product according to 1H NMR. MS: m / z: 422 (M + H); Purity (HPLC): 95.2%; 1H NMR (500 MHz, chloroform-d) δ ppm 13.34 (s, 1H) 7.81 (s, 1H) 7.54 - 7.65 (m, 4H) 7.47 (s, 2 H) 5.82 (s, 2H) 5.02 (brs, 2H).

twenty

(ii) 5 (3,4-Dichlorophenyl) imino4 [[3 (trifluoromethyl) phenyl] methyl] 1,2,4-thiadiazolidin3one

To a solution of 1 - [(3,4-dichlorophenyl) carbamothioyl] -1 - [[3- (trifluoromethyl) phenyl] methyl] urea (42 mg, 0.1 mmol) in 0.5 ml of EtOH at 0 ° C , bromine (16 mg in 0.5 ml EtOH) was added dropwise. HPLC-MS analysis revealed a conversion

25 almost complete to product after 30 min stirring. The reaction was worked up after 1.5 h. Water (3 ml) was added and the resulting aqueous phase was extracted with Et2O (3x15 ml). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo to yield 43.5 mg of crude material (approximately 90% purity). The material was purified by preparative HPLC (basic conditions) and MS Prep XTerra, C18 column, 5 mm, 19x50 mm, flow 25 ml / min, NH4HCO3 50 mM pH10 / ACN, 5-97% ACN in 6 min; the

30 fractions were collected based on the UV signal (254 nm) to give 21.7 mg of product (52%). HPLC purity: 98.5%; MS: m / z: 420 (M + H); 1H NMR (500 MHz, chloroform-d) δ ppm 7.81 (s, 1 H) 7.70 (d, J = 7.81 Hz, 1 H) 7.60 (d, J = 7.81 Hz, 1H) 7.49 (t, J = 7.69Hz, 1H) 7.40 (d, J = 8.55Hz, 1H) 7.06 (d, J = 2.44Hz, 1H ) 6.79 (dd, J = 8.55, 2.44 Hz, 1H) 5.04 (s, 2H).

35 Example 2

The following compounds (compounds (c) and (e)) were prepared, or can be prepared, using the procedures described earlier in this specification.

40 a) 5- (3,4-Dichlorophenyl) imino-4 - [(4-methoxyphenyl) methyl] -1,2,4-thiadiazolidin-3-one

image55

image56

;

b) 4 - [(4-Chlorophenyl) methyl] -5- (3,4-dichlorophenyl) imino-1,2,4-thiadiazolidin-3-one

Image57

;

Image58

c) 5- (3,4-Dichlorophenyl) imino-4 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazolidin-3-one

image59

1H NMR (500 MHz, methanol-d4) δ ppm 7.48 (d, J = 8.55 Hz, 1 H) 7.39 (ddd, J = 11.35, 7.81, 1.83 Hz, 1 H) 7.22 - 7.31 (m, 2H) 7.15 (d, J = 2.44 Hz, 1H) 6.92 (dd, J = 8.55, 2.69 Hz, 1H ) 4.97 (s, 2H). ESI MS m / z = 388 [M + H] +;

d) 5- (3,4-Dichlorophenyl) imino-4 - [(3-fluorophenyl) methyl] -1,2,4-thiadiazolidin-3-one

image60

10

;

e) 5- (3,4-Dichlorophenyl) imino-4- [phenyl) methyl] -1,2,4-thiadiazolidin-3-one

fifteen

image61

1H NMR (500 MHz, methanol-d4) δ ppm 7.47 (d, J = 8.55 Hz, 1 H) 7.45 (d, J = 7.32 Hz, 2 H) 7.35 (t, J = 7.32 Hz, 2 H) 7.28

- 7.33 (m, 1H) 7.14 (d, J = 2.44 Hz, 1H) 6.92 (dd, J = 8.55, 2.44 Hz, 1H) 5.01 ( s, 2H); ESI MS m / z = 352 [M + H] +.

f) 5- (3,4-Dichlorophenyl) imino-4-phenethyl-1,2,4-thiadiazolidin-3-one

twenty

image62

image63

Oh

;

g) 4- [2 - [(4-Chlorophenyl) -methyl-amino] ethyl] -5- (3,4-dichlorophenyl) imino-1,2,4-thiadiazolidin-3-one

image64 Cl

N

Cl

image65 N

N

S

N

Cl O

H

;

25

h) 4- [2- (4-Chlorophenyl) sulfanylethyl] -5- (3,4-dichlorophenyl) imino-1,2,4-thiadiazolidin-3-one

;

30 i) 3 - [[(5- (3,4-Dichlorophenyl) imino-3-oxo-1,2,4-thiadiazolidin-4-yl] methyl] -N-methylbenzamide

image66

image67 Cl

ON Cl HN

N Y

N OH

;

5 j) 5 - [(6-Chloro-3-pyridyl) imino] -4 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazolidin-3-one

Image68 N

Cl

N F N

Y N

F OH

;

k) 4 - [[4 - [(3,4-Difluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] amino] benzonitrile 10

N

N F

N

Y N

F

O H

image69

l) 4 - [(3,4-Difluorophenyl) methyl] -5- [4- (trifluoromethyl) phenyl] imino-1,2,4-thiadiazolidin-3-one

image70 F

F F

N F

N

Y N

F

Oh

;

15 m) 4 - [(3,4-Difluorophenyl) methyl] -5- [4- (trifluoromethoxy) phenyl] imino-1,2,4-thiadiazolidin-3-one

image71 FF

F O

N F

N

Y N

F

O H

;

twenty

n) 3- [5- (3,4-Dichlorophenyl) imino-3-oxo-1,2,4-thiadiazolidin-4-yl] methyl] benzonitrile

image72 Cl N

N

Cl

N

Y N

O H

;

image73

image74

image75

image76

image77

image78

Example 4

The following compounds (compounds (a) to (f) and (j) to (r)) were prepared, or can be prepared, using the procedures described above in the specification.

a) 4-fluoro-N- [3-oxo-2 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazol-5-yl] benzamide

image79 FF

H

image80 N

F N

NO

MS: [M + H]: 398.0; HPLC purity: 100%; 1H NMR (500 MHz, methanol-d4) δ ppm: 8.19 (dd, J = 8.79, 5.37 Hz, 2H) 7.69 (s, 1H) 7.62 - 7.67 ( m, 2H) 7.56-7.62 (m, 1H) 7.26 (t, J = 8.79Hz, 2H) 4.94 (s, 2H).

b) 2- (4-fluorophenyl) -N- [3-oxo-2 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazol-5-yl] acetamide

image81

image82

OR

fifteen

MS: [M + H]: 412; HPLC purity: 100%; 1H NMR (500 MHz, methanol-d4) δ ppm 7.64 (s, 1H) 7.60 - 7.63 (m, 1H) 7.57

- 7.60 (m, 1H) 7.53 - 7.57 (m, 1H) 7.31 (dd, J = 8.55, 5.37 Hz, 2H) 7.06 (t, J = 8.79 Hz, 2H) 4.95 (s, 2H) 3.86 (s, 2H);

20 c) 4-chloro-N- [2 - [(3,4-difluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide

image83

OR

MS: [M + H]: 382.0; HPLC purity: 100%; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.10 (d, J = 8.79 Hz, 2H) 7.62 (d, 25 J = 8.30 Hz, 2H) 7.38 - 7 , 49 (m, 2H) 7.21 (ddd, J = 6.23, 4.15, 2.08 Hz, 1H) 4.78 (s, 2H);

d) 4-chloro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide

image84

OR

MS: [M + H]: 364.0; HPLC purity: 100%; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.10 (d, J = 8.55 Hz, 2H) 7.62 (d, J = 8.79 Hz, 2H) 7.41 (dd, J = 8.67, 5.49 Hz, 2H) 7.21 (t, J = 8.91 Hz, 2H) 4.78 (s, 2H);

image85

e) 4-chloro-N- [2 - [(4-chlorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] -benzamide

image86

MS: [M + H]: 380.0; HPLC purity: 100%; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.10 (d, J = 8.55 Hz, 2H) 7.63 (d, J = 8.55 Hz, 2H) 7.44 (d, J = 8.55 Hz, 2H) 7.38 (d, J = 8.55 Hz, 2H) 4.79 (s, 2H);

f) 4-Chloro-N- [2- [2- (phenoxy) ethyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide

image87 Cl

H

image88 N

OR

image89 S

image90 N

OR

NO

MS: [M + H]: 377.0; HPLC purity: 100%; 1H NMR (500 MHz, DMSO-d6) δ ppm 8.12 (d, J = 8.55 Hz, 2H) 7.63 (d, J = 8.79 Hz, 2H) 7.30 (dd, J = 8.55, 7.32 Hz, 2H) 6.93 - 6.99 (m, 3H) 4.20 (t, J = 5.00 Hz, 2H) 3.97 (t, J = 5.01 Hz, 2H); 15 g) 4-Chloro-N- [2- [2 - [(4-chlorophenyl) -methyl-amino] ethyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide

Cl

;

h) 4-Chloro-N- [2- [2- (4-chlorophenyl) sulfanylethyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide 20

Cl

;

i) 3,4-Dichloro-N- [2- [1- (4-fluorophenyl) cyclopropyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide

OR

;

25 j) 3,4-Dichloro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide

OR

image91

image92

image93

image94

image95

1H NMR (500 MHz, DMSO-d6) δ ppm 4.78 (s, 2H) 7.18 - 7.24 (m, 2H) 7.38 - 7.43 (m, 2H) 7.83 (d, J = 8.30 Hz, 1H) 8.02 (dd, J = 8.55, 1.95 Hz, 1H) 8.24 (d, J = 1.95 Hz, 1H);

k) N- [2 - [(4-Fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] -4-methoxy-benzamide 5

MS: [M + H]: 360; HPLC purity: 95%; 10 L) 2,6-Dichloro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide

MS: [M + H]: 398; HPLC purity: 95%; 15 m) 2,4-Dichloro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide

MS: [M + H]: 398; HPLC purity: 98% 1H NMR (500 MHz, DMSO-d6) δ ppm 4.80 (s, 2H) 7.19 - 7.24 (m, 2H) 7.39 7.44 (m, 2H ) 7.60 (dd, J = 8.42, 2.08 Hz, 1H) 7.79 (d, J = 1.71 Hz, 1H) 7.91 (bs, 1H) 13.71 ( bs, 1H);

n) N- [2 - [(4-Fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] -4- (trifluoromethoxy) -benzamide

image96

image97

image98

F

F image99

F

F image100

image101 OR

H

image102 N

N

OR

N

OR

MS: [M + H]: 414; HPLC purity: 100%; o) N- [2 - [(4-Fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] -3,5-bis (trifluoromethyl) -benzamide

image103

image104 F FF

F image105

F

H

F

Image106 N

N F

OR

NO

MS: [M + H]: 466; HPLC purity: 95%; p) 3,4-Difluoro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide

image107

10

MS: [M + H]: 366; HPLC purity: 100%; q) 2-Chloro-6-fluoro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide

F image108

image109 Cl

H

image110 N

N FO

N

OR

MS: [M + H]: 382; HPLC purity: 100%; and r) 3,5-Difluoro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide

twenty

image111

MS: [M + H]: 366; HPLC purity: 95%.

Compounds 4j-4r were synthesized starting from a compound of formula III by reaction with compounds of formula IV in which L2 is chlorine and W1 is -C (O) - (substituted benzoyl chloride).

Compounds 4j-4r were synthesized as a small collection of compounds as follows:

30 5-amino-2- (4-fluoro-benzyl) - [1,2,4] thiadiazol-3-one and pyridine were mixed in 400 µl of acetonitrile. The acid chloride in 100 µl of acetonitrile was added. The reaction stirred overnight. 50 µl of 2M KOH was added to hydrolyze the disubstituted by-product. After 1 day, the reaction was acidified with 100 µl of TFA, diluted to 2 ml with DMSO / methanol / water, and purified by reverse phase chromatography (ACE C8, 5 µm, 21x50 mm, flow 25 ml / min , gradient: water + 0.1% TFA / acetonitrile, over 6 minutes).

image112

Example 5

a) 5- (3,4-Dichlorophenyl) imino-4- (2-phenoxyethyl) -1,2,4-thiadiazolidin-3-one; and b) 5- (3,4-Dichloro-phenylamino) -2- (2-phenoxyethyl) - [1,2,4] thiadiazol-3-one

image113 Cl image114 OR image115 S

N

N Image116

N

N

Cl

OR

Or Cl

N Y

image117 N OH Cl

5a 5b

10 (i) (2-phenoxyethyl) urea

2-Phenoxyethylamine (137 mg, 1 mmol) and urea (300 mg, 5 mmol) were placed in a 2 ml microwave vial. Conc. HCl were added. (200 µl) and water (500 µl) and the mixture was heated at 150 ° C for 30 min under microwave irradiation. After cooling, the vial was filled with a white precipitate. The solid was collected by filtration and washed with several portions of water. After drying under vacuum in a vacuum desiccator, 167 mg (93%) of product was isolated as a white crystalline material. HPLC-MS revealed that the product consisted of a mixture of 67% product and 33% dialkylated product. Purification by flash chromatography (silica, 4-5% MeOH in CH2Cl2) gave 79 mg (44%) of pure product as a white solid. 1H NMR (500 MHz, methanol-d4) δ ppm 7.28 (dd, J = 8.91, 7.20 Hz, 2H) 6.90 -6.99 (m, 3H) 4.02 (t , J = 5.37 Hz, 2H) 3.51 (t, J = 5.37 Hz, 2

20 H).

(ii)

(a) 1 [(3,4-Dichlorophenyl) carbamothioyl] 1 (2-phenoxyethyl) urea

(b)

1 [(3,4-Dichlorophenyl) carbamothioyl] 1 (2-phenoxyethyl) urea

To a solution of (2-phenoxyethyl) -urea (79 mg, 0.44 mmol, from step (i) above) in dry THF (2 ml), n-BuLi was added dropwise. The mixture was stirred at room temperature for 15 min and then 3,4-dichlorophenyl isothiocyanate (89 mg, 044 mmol) in dry THF (2 mL) was added dropwise. After 1.5 h, HPLC revealed the almost complete disappearance of the starting material. A saturated solution of NaHCO3 (5 ml) and EtOAc were added.

30 (20 ml) and the phases were separated. The aqueous phase was extracted with another 20 ml of EtOAc. The combined organic phase was washed with water (5 ml), brine (5 ml) and dried over MgSO4. Concentration in vacuo gave 158 mg of a yellow oil. An HPLC-MS revealed two products with the expected molecular weight, m / z = 384.

Purification by flash chromatography (silica, 30% EtOAc in n-hexane) gave the products: a: 29 mg, Tr = 2.875 min (ACE, 10-97% CH3CN in 3 min, 1 ml / min): 73% purity, m / z = 384; b: 34 mg (Fr 11-16) Tr = 2.908 min (ACE, 10-97% CH3CN in 3 min, 1 ml / min): 97% purity, m / z = 384.

These two products were not further characterized. They were cycled in two separate experiments.

40 (iii) (a) 5 (3,4-Dichlorophenyl) imino4 (2phenoxyethyl) 1,2,4-thiadiazolidin3one;

(b) 5 (3,4-Dichlorophenylamino) 2 (2-phenoxyethyl) [1,2,4] thiadiazol3one

The cyclization of the compounds of steps (ii) (a) and (ii) (b) to obtain the products was done according to the process shown in step (ii) of Example 1. Purification by RP-HPLC gave the desired compounds.

5 (a): MS: [M + H]: 385.0; HPLC purity: 97%; 1H NMR (500 MHz, DMSO-d6) δ ppm 7.42 (d, J = 8.67 Hz, 1H) 7.24 7.31 (m, 2H) 7.05 (d, J = 2, 44 Hz, 1H) 6.99 - 7.03 (m, 2H) 6.92 (tt, J = 7.32, 1.04 Hz, 1H) 6.87 (dd, J = 8.67 , 2.52 Hz, 1H) 4.10-4.16 (m, 2H) 3.95-4.02 (m, 2H);

5 (b) b: MS: [M + H] 385.0; HPLC purity: 100%; 1H NMR (500 MHz, DMSO-d6) δ ppm 11.01 (s, 1 H) 8.05 (d, J = 2.20 Hz, 1 H) 7.62 (d, J = 8.79 Hz, 1H) 7.44 (dd, J = 8.79, 2.44 Hz, 1H) 7.27-7.34 (m, 2H) 6.93-6.99 (m, 3H) 4 , 17 (t, J = 4.88 Hz, 2H) 4.00 (t, J = 4.88 Hz, 2H).

55

image118

image119

Example 6

4-Benzohydril-5- (3,4-dichlorophenyl) imino-1,2,4-thiadiazolidin-3-one

image120 Cl

5

The next compound was formed using the same methods described in Examples 1 and 5, with the appropriate starting materials, except the last cyclization step in which EtOAc was used instead of EtOH as the solvent.

MS: m / z = 428 [M + H] +; HPLC purity: 98% (ACE), 96% (XTerra); 1H NMR (500 MHz, DMSO-d6) δ ppm 10.95 (bs, 1H) 8.02 (bs, 1H) 7.61 (d, J = 8.79Hz, 1H) 7.38 - 7.45 (m, 5H) 7.33-7.38 (m, 2H) 7.22 (d, J = 7.32 Hz, 4H) 6.62 (s, 1H).

Example 7

15 a) 4-Chloro-N- [4 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] benzamide

image121

image122

Cl

20 (i) N (Carbamoylcarbamothioyl) 4-chlorobenzamide

4-Chlorobenzoyl isothiocyanate (395 mg) and 600 mg of urea (5 equiv.) Were mixed in 30 ml of acetone and stirred at reflux for 1 day. The reaction was concentrated and the residue was suspended in diethyl ether. The residue was collected by filtration and washed with diethyl ether. The white solid was dissolved in ethyl acetate (10 ml) and the resulting solution was

Washed with water (10 ml) and brine (10 ml); dried over MgSO4, filtered and concentrated to a white solid (0.35 g, 1.4 mmol, 70% yield).

(ii) 4CloroN (3oxo1,2,4thiadiazol5yl) benzamide

The N- (carbamoylcarbamothioyl) -4-chloro-benzamide (350 mg) from step (i) above was mixed with 50 ml of ethyl acetate. Bromine (224 mg) in 5 ml of ethyl acetate was added. After 30 minutes, 10 ml of water and 10 ml of methanol were added. The mixture was concentrated and the residue was triturated with water / methanol and dried in vacuo to give the product as a white solid, 0.25 g, 0.98 mmol, 70% yield.

35 (iii) 3,4-DichloroN [4 [(4-fluorophenyl) methyl] 3oxo1,2,4-thiadiazolidin-5ilidene] benzamide

4-Chloro-N- (3-oxo-1,2,4-thiadiazol-5-yl) benzamide (50 mg, 0.20 mmol, 1 equiv.) And 55 mg (0.40 mmol, 2 equiv. .) of potassium carbonate in 5 ml of DMF. 4-Fluorobenzyl bromide (38 mg, 0.20 mmol, 1 equiv.) In 2 ml of DMF was added dropwise. The mixture was stirred 15 min and then the reaction mixture was diluted with

40 100 ml of ethyl acetate and 100 ml of water. The organic phase was washed 2x with 100 ml of water and 50 ml of brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica, 40% EtOAc in hexane), to give the product as a white solid, 8 mg, 22 µmol, 11%. 1H NMR (500 MHz, DMSO-d6) δ ppm 5.17 (s, 2H) 7.16 - 7.22 (m, 2H) 7.50 - 7.56 (m, 2H) 7.61 - 7.65 (m, 2H) 8.19 8.23 (m, 2H) 10.46 (brs, 1H); MS: [M + H] +; HPLC purity: 93%.

The following compounds can be prepared according to the methods disclosed in Example 7 (a):

image123

b) 4-Chloro-N- [4 - [(4-chlorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] benzamide

image124 Or Cl image125 NN

S

OR

N H Cl

5 c) 4-Chloro-N- [3-oxo-4 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazolidin-5-ylidene] benzamide

image126 FF

F

image127 OR

N

N

S

OR

N H Cl

;

d) N- [4 - [(3-Fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] -4- (trifluoromethyl) benzamide 10

F image128

OR

N image129

N

S

OR

N

F

H F

F

;

e) N- [4 - [(3-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] -3,5-bis (trifluoromethyl) benzamide

F image130

image131 OR

N

NF

F

S

OR

N

F

H FF

F

;

fifteen

f) N- [4 - [(3,4-Dichlorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] -3,4-difluorobenzamide

image132 Cl O Cl N image133

SF

OR

N

H

F

;

twenty

and

g) 3,4-Dichloro-N- [4 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] benzamide

image134 OF image135 NNS Cl

OR

N H Cl

.

25

Example 8

The following compounds (a to d, f, k, l, or a r and w) were prepared, or can be prepared, using the procedures described in Example 1, except that in step (i):

(I) no base is used in the first step to ensure coupling of the isothiocyanate derivative with the primary nitrogen of the urea derivative; (ii) 20% DMF in acetonitrile is used as solvent; and (iii) the reaction mixture is stirred 48 h at 80 ° C.

10 a) 1,5- (3,4-Dichlorophenylamino) -2- (4-methoxybenzyl) - [1,2,4] thiadiazol-3-one

image136

15 1H NMR (500 MHz, DMSO-d6) δ ppm 3.74 (s, 3H) 4.72 (s, 2H) 6.92 (q, J = 5.13 Hz, 2H) 7.24 (q, J = 5.13 Hz, 2H) 7.45 (dd, J = 8.79, 2.44 Hz, 1H) 7.62 (d, J = 8.79 Hz, 1H) 8 , 04 (d, J = 2.44 Hz, 1H); ESI MS m / z = 382 [M + H] +; HPLC purity: 100%;

b) 1,5- (3,4-Dichlorophenylamino) -2- (4-chlorobenzyl) - [1,2,4] thiadiazol-3-one 20

image137

1H NMR (500 MHz, DMSO-d6) δ ppm 4.81 (s, 2H) 7.32 (d, J = 8.55 Hz, 2H) 7.42 - 7.47 (m, 3H) 7.63 (d, J = 8.79Hz, 1H) 8.05 (d, J = 2.44Hz, 1H); MS: ESI MS m / z = 386 [M + H] +; HPLC purity: 95%;

c) 1,5- (3,4-Dichlorophenylamino) -2- (3,4-difluorobenzyl) - [1,2,4] -thiadiazol-3-one

F image138 SH

N

image139 N

N

F

OR image140 Cl

Cl

1H NMR (500 MHz, DMSO-d6) δ ppm 4.80 (s, 3H) 7.14 - 7.17 (m, 1H) 7.36 - 7.47 (m, 3H) 7, 63 (d, J = 8.79Hz, 1H) 8.05 (d, J = 2.44Hz, 1H); ESI MS m / z = 388 [M + H] +; HPLC purity: 100%;

d) 1,5- (3,4-Dichlorophenylamino) -2- (3-fluorobenzyl) - [1,2,4] thiadiazol-3-one

image141

35

Cl

1H NMR (500 MHz, DMSO-d6) δ ppm 4.83 (s, 2H) 7.09 - 7.18 (m, 3H) 7.38 - 7.48 (m, 2H) 7.63 (d, J = 8.79 Hz, 1H)

8.05 (d, J = 1.22 Hz, 1H); MS: 371 [M + H] +; HPLC purity: 97%;

40

image142

e) 1,5- (3,4-Dichlorophenylamino) -2- (benzyl) - [1,2,4] thiadiazol-3-one

image143

Cl

;

f) 5- (3,4-Dichlorophenylamino) -2-phenethyl- [1,2,4] thiadiazol-3-one

image144

1H NMR (500 MHz, DMSO-d6) δ ppm 2.89 (t, J = 7.08 Hz, 2H) 3.87 (t, J = 7.08 Hz, 2H) 7.19-7, 34 (m, 5H) 7.42 (dd, 10 J = 8.79, 2.44 Hz, 1H) 7.62 (d, J = 8.79 Hz, 1H) 8.02 (d, J = 1.71 Hz, 1H); MS: 367 [M + H] +; HPLC purity: 97%;

g) 2- [2 - [(4-Chlorophenyl) -methyl-amino] ethyl] -5 - [(3,4-dichlorophenyl) amino] -1,2,4-thiadiazol-3-one

image145 N Image146 image147

SH

N

N image148

N

Cl O Cl

Cl

;

h) 2- [2- (4-chlorophenyl) sulfanylethyl] -5 - [(3,4-dichlorophenyl) amino] -1,2,4-thiadiazol-3-one

image149 S image150 SH

N

N

N

Cl

Or Cl

Cl

;

I) 3 - [[5 - [(4-Chlorophenyl) amino] -3-oxo-1,2,4-thiadiazol-2-yl] methyl] -N-methyl-benzamide

OR

image151

j) 5 - [(6-Chloro-3-pyridyl) amino] -2 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazol-3-one

image152

Cl

;

image153

k) 2 - [(3,4-Difluorophenyl) methyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one

F image154 S

H

N

N N F

OR

F FF

1H NMR (500MHz, DMSO-d6) δ ppm 4.82 (s, 2H) 7.13 - 7.21 (m, 1H) 7.36 - 7.48 (m, 2H) 7, 72-7.77 (m, 2H) 7.78 7.84 (m, 2H); MS: 388 [M + H] +; HPLC purity: 95%;

l) 2 - [(3,4-Difluorophenyl) methyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one

F image155 SH

N

N N

F

OR

F O FF

10 1H NMR (500 MHz, DMSO-d6) δ ppm 4.79 (s, 2H) 7.12 -7.20 (m, 1H) 7.33 - 7.49 (m, 4H) 7, 70 (d, J = 9.03 Hz, 2H); MS: 404 [M + H] +; HPLC purity: 100%; 15 m) 5 - [(4-Chlorophenyl) amino] -2- [1- (4-chlorophenyl) cyclopropyl] -1,2,4-thiadiazol-3-one

Image156

Cl

;

n) 5 - [(3,4-Dichlorophenyl) methylamino] -2 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazol-3-one

Image157

o) 2 - [(4-Methoxyphenyl) methyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one

image158

FF

1H NMR (500 MHz, DMSO-d6) δ ppm 3.74 (s, 3H) 4.74 (s, 2H) 6.89-6.97 (m, 2H) 7.22-7, 29 (m, 2H) 7.71-7.76 (m, 2H) 7.76-7.82 (m, 2H); MS: 382 [M + H] +; HPLC purity: 100%; 30 p) 2 - [(4-chlorophenyl) methyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one

image159

FF

image160

1H NMR (500 MHz, DMSO-d6) δ ppm 4.82 (s, 2H) 7.29 - 7.36 (m, 2H) 7.41 - 7.47 (m, 2H) 7.73 - 7.77 (m, 2H) 7.77 7.83 (m, 2H); MS: 387 [M + H] +; HPLC purity: 100%;

q) 2 - [(3-Fluorophenyl) methyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one

5

1H NMR (500 MHz, DMSO-d6) δ ppm 4.84 (s, 2H) 7.10 - 7.20 (m, 3H) 7.37 - 7.46 (m, 1H) 7.72 - 7.78 (m, 2H) 7.77 7.84 (m, 2H); MS: 370 [M + H] +; HPLC purity: 100%;

10

r) 2- [Phenylethyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one

image161

image162

15 1H NMR (500 MHz, DMSO-d6) δ ppm 2.90 (t, J = 7.08 Hz, 2H) 3.88 (t, J = 7.08 Hz, 2H) 7.19 - 7 , 34 (m, 5H) 7.71-7.76 (m, 2H) 7.76-7.82 (m, 2H); MS: 360 [M + H] +; HPLC purity: 95%;

s) 2 - [(4-Methoxyphenyl) methyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one

image163 S

H

N

N N

OR

OR image164 FO FF

;

20 t) 2 - [(4-Chlorophenyl) methyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one

image165 S

H

N

N N

Cl O F O FF

;

25

u) 2 - [(3-Fluorophenyl) methyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one

F Image166 SH image167

N

N N

O F O FF

;

30

image168

v) 2- [Phenylethyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one

image169

FF

; and

5 w) 4 - [[2 - [(3,4-Difluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] amino] benzonitrile

F image170 SH

N

N image171

N

F

OR

N

1H NMR (500 MHz, DMSO-d6) δ ppm 4.82 (s, 2H) 7.13 - 7.20 (m, 1H) 7.36 - 7.48 (m, 2H) 7.75 - 7.82 (m, 2H) 7.82 7.88 (m, 2H); MS: 345 [M + H] +; HPLC purity: 95%.

Biological tests

Descriptions of cancer cell lines can be obtained including source, tumor type, and

15 morphology, from the American Type Culture Collection (ATCC) or on its website (www.atcc.org). Cell lines are from both primary tumors and metastatic sites (eg MCF-7, MDA-MB231, HT-29, SKOV-3 and PC-3, among others tested).

Test A

twenty

Cell proliferation test

Reagents:

25 Dulbecco's Modified Eagle's Medium (D-MEM) +1000 mg / L glucose + GlutaMAX ™ 1 + pyruvate (Gibco # 21885025) V / V Fetal Bovine Serum (Gibco 10500-064) 5-bromo-2-deoxyuridine (BrdU) Dimethyl sulfoxide 30 (DMSO)

The PC-3 cancer cell lines were propagated in D-MEM (Gibco 21885) supplemented with 10% fetal calf serum. 15000 cells were seeded per well in 96-well plates and incubated overnight. The culture medium was changed to serum free D-MEM for 24 hours. The culture medium was then changed to serum-free D-MEM containing 0.2% DMSO as vehicle control, or 0.3, 0.6, 1.2, or 2.5 µM (or 1.25 , 2,5, 5,

10 µM (as indicated in Table 1 below)) of the selected compounds from Example 1 to Example 8, in 0.2% DMSO per quadruple. After 18 hours of incubation, BrdU was added according to the manufacturer's recommendations. After 6 hours of incubation in the presence of BrdU, the culture medium was removed and the incorporation of BrdU was measured using the "Cell Proliferation ELISA, BrdU colorimetric" from Roche (11647229001), according to the manufacturer's recommendations.

40

Results

The proliferation rate of PC-3 cells is reduced by relevant concentrations of the test compounds, measured by the incorporation of BrdU. For example, in the test above, the compounds

45 selected from Example 1 to Example 8, with respect to the vehicle control (which presents a BrdU incorporation of 1 unit), presented the following (approximate) BrdU incorporation units, at the concentrations indicated in Table 1.

Table 1

Example (#)

Incorporation of BrdU Units Conc. (ΜM)

1

0.39 0.6

2 C

0.34 0.6

2e

0.17 5

2 g

0.14 10

3

0.70 10

4th

0.309 10

4b

0.72 10

4c

0.393 10

4d

0.612 10

4e

0.355 10

4i

0.10 5

4l

0.20 10

4m

0.23 10

4n

0.17 2.5

4th

0.28 10

4p

0.26 10

5th

0.37 10

5b

0.14 10

6

0.42 1.25

8a

0.04 2.5

8b

0.18 2.5

8c

0.07 1.25

8f

0.08 5

8k

0.04 5

8l

0.10 5

8p

0.07 5

8q

0.15 5

8r

0.58 5

8w

0.28 5

Test B

5 In vivo mouse model Test 1

5 week old athymic BALB / cA hairless mice were supplied by Taconic (Denmark) and kept under barrier conditions for one week acclimatization. At 6 weeks, 17 mice were injected subcutaneously into their flank with 1.8 x 106 human breast cancer cells MDA-MB-231 (LGC

10 Promochem-ATCC) in a 50/50 v / v solution of Phosphate Buffer Saline (PBS) (Gibco 10010-015, Invitrogen) Matrigel HC (BD Biosciences).

After 11 days, palpable tumors were observed in 16 mice. 2 mice were sacrificed and the tumors were dissected and examined. Two groups of 7 mice each were treated once daily with injections.

Intraperitoneal 15 1-10 mg / kg body weight of the test compound in 79% PBS / 15 20% Solutol HS (BASF) / 1% DMSO or vehicle control, respectively, for 5-30 days. The mice were sacrificed by cervical dislocation and the tumors were dissected.

image172

Histology

Tumor tissue was fixed overnight in PBS (containing 4% w / v paraformaldehyde (Scharlau PA0095, Sharlau Chemie SA, Spain) at +4 ° C. Tumor tissue was stored cold by incubation for 24 hours

5 in PBS containing 30% w / v sucrose (BDH # 102745C (www.vwr.com) at +4 ° C, and embedded in Tissue-Tek embedding medium (Sakura Finetek Europe BV, The Netherlands). 10 µm cryosections were generated and stained with Mayers hematoxylin (Dako) for 5 min, and 3 x 10 min. In tap water Slides were mounted using Dako faramount aqueous mounting medium and examined using a Nikon Eclipse TS 100 microscope , documented using a Nikon coolpix 4500.

The morphology of the tumors of the mice treated with test compound and vehicle was analyzed by microscopic examination of the cryosections stained with hematoxylin.

In vivo mouse model Test 2

The above test procedure was followed, but 16 mice (instead of 17) were injected subcutaneously.

After 6 days palpable tumors were observed in all 16 mice. Two groups of 8 mice each were treated once daily with intraperitoneal injections of 7.5 mg / kg body weight of the test compound in 79% PBS / 20% Solutol HS (BASF) / 1% DMSO. or vehicle control, respectively, for 27 days. Tumor size was measured with caliper every third day.

The tumor area results in the first group of mice (treated with test compound) were compared against the second group of mice ("untreated") after a certain number of days.

As will be appreciated, Test B described above provides one of many possible in vivo xenograft models. Modifications of test B above can be made (for example changing some or all of: the formulation of the test compounds, the cell line, and the type of mice used).

Test C

Activation of AMPK and S79 ACC

Test compound:

Compounds selected from Examples 1, 4 to 6 and 8. A 10 µM stock solution was prepared by dissolving the compound in 100% DMSO.

Cell line and cell culture:

Human PC3 cells were purchased from LGC Promochem-ATCC (ATCC catalog # CRL-1435). PC3 cells were maintained in Dulbecco's modified Eagle's medium (Gibco 21885) containing 5% fetal bovine serum (Gibco 10500-064), 25 µg / ml gentamicin (Gibco 20 15750) and 1x nonessential amino acids (Gibco 11140) . The cells were incubated in a humidified atmosphere of 5% CO2 at 37 ° C and passed every 3 days by trypsinization. For

For the experiments, PC3 cells were cultured in complete medium with 10% fetal bovine serum in 60 mm diameter plates, developed at 70-80% confluence, and cultured in serum-free Dulbecco's modified Eagle's medium for 5 hours. . The cells were then treated with 10 µM of the compound of Example 1 for 24 hours. The final DMSO concentration did not exceed 0.1%, which did not affect the phosphorylation of AMPK or eEF2 (0.1% DMSO was used as a control).

Western Blot Analysis:

PC3 cells were lysed in buffer (100 mM TRIS pH 6.8, 2% w / v sodium dodecyl sulfate (SDS), 10 mM NaF, 10 mM β-glycerophosphate, 1 mM sodium vanadate) . Cellular debris is

55 were removed by centrifugation at 14,000 X g for 15 min at 4 ° C and the resulting supernatant was used for Western blotting. Protein concentrations of the lysates were measured using a BCA protein test kit (Perforated # 23225). For the Western blot, 15 µg of protein was loaded into each well of a 4-12% bis / tris gel for the detection of AMPK or S-79 ACC (Criterion precast gel Bio-Rad # 345-0117), and was executed in accordance with the manufacturers recommendation. The gels were applied on cellulose filters (Hybond-C extra Amersham # RPN203E). Filters were blocked in 20 mM TRIS pH 7.5, 137 mM NaCl, 25% v / v Tween20 and 5% w / v skim milk powder for 30 minutes. Filters were incubated overnight in blocking solution with phospho-AMPK (Thr172) or phospho-acetyl CoA carboxylase (cell signaling # 2531 and # 3661), or with a pan-AMPK antibody (cell signaling # 2532). Filters were washed in 20 mM TRIS pH 7.5, 137 mM NaCl, 25% v / v Tween20, 3 x 5 min. The filters are

65 incubated in blocking solution with secondary antibody, peroxidase-conjugated goat anti-rabbit IgG (Jackson ImmunoResearch # 111-035-003) at room temperature for 1 hour. Filters were washed as before for 3x10 minutes. The signal was developed with the SuperSignal West Dura ECL Kit (Perforated # 1859024) and exposed to Hyperfilm ECL Amersham # 28906837).

image173

Results

5 The result of the Western blot showed that the compounds selected among examples 1, 4 to 6 and 8 stimulated the phosphorylation of Thr-172 of the ε subunit of AMPK (compared to the control), and increased the production of phosphorylated acetyl coenzyme A (an AMPK substrate), as depicted in Figures 1 and 2.

Test D

In vitro cytotoxicity data with various cell lines in a 96-well plate

SRB cytotoxicity study

Cells were seeded and grown in the presence of varying concentrations of the test compound (s) over a period of 3 days (72 hours). The cells were then fixed to the plate and exposed to sulphorhodamine dye B (SRB). Varying amounts of proliferation inhibition produce a standard curve from which the IC50 value was determined.

Section A: Plating the cells on the plate

96-well plates were seeded in this test at a correspondingly determined seeding density for each cell line. 25 Adherent cells:

1.

Harvest the cells and count them. All procedures associated with the harvesting and preparation of cell suspensions will be performed in a class II hood.

2.

A sterile 96-well cell culture plate (Microtest flat bottom tissue culture plate, Falcon 3072) is used in the test.

3.

Dilute cells to the appropriate seeding density.

Four.

Add 100 µl of the cell suspension to wells B1 to G12.

5.

Add 100 µl of medium to all blank wells (A1 to A12, H1 to H12).

35 6. Incubate plates overnight at 37 ° C in a 5% CO2 incubator.

Cells in suspension:

1.

Harvest the cells and count them. All procedures associated with the harvesting and preparation of cell suspensions will be performed in a class II hood.

2.

A sterile 96-well cell culture plate (Microtest flat bottom tissue culture plate, Falcon 3072) is used in the test.

3.

Dilute cells to the appropriate seeding density.

Four.

Add 100 µl of the cell suspension to wells B1 to G12.

45 5. Add 100 µl of medium to all blank wells (A1 to A12, H1-H12).

6. Add drugs to cells immediately after plating.

Section B: Addition of Compound (s) to Cells

7.

Prepare the plate for the test compound (s) and transfer the diluted compound to the test plate prepared in section A.

8.

On the compound plate add 100 µl of cell culture medium to wells B3-G3 to B10-G10.

9.

Dilute the test items to 250 µM in the cell culture medium in a separate tube, which will make the

50 µM initial concentration. The stock concentration of the test compound (s) is 55 10 mM, therefore dilute 1:40 to obtain a concentration of 250 µM.

10.

Add 200 µl of the diluted drug lot to empty wells B2 through G2, and mix by pipetting up and down 3 times.

eleven.

Transfer 100 µl from each of these wells (using a multichannel pipet) to wells B2-G2, etc., and continue to dilute 1: 2 throughout the plate up to column 10. Discard the excess 100 µl from each row in column 10. Column 11 contains control DMSO. Row 12 contains 100 µl of blank medium.

12.

DMSO control same as drug: Dilute DMSO 100% in medium. Pipette 100 µl into empty row 11 of the compound plate. Of this, 25 µl will be added to the test plate containing the cells, giving a final concentration of 0.5%. Blank control: Pipette 100 µl of blank medium to row 1 and 12, 25 µl of this will be added to the test plate containing the cells.

65 13. Using a new set of tips, transfer the drug dilutions from the compound plate to the test plate containing the cells (25 µl of diluted drug transferred to the 100 µl cells in the test plate; volume final will be 125 µl). Start with the lowest drug concentrations.

image174

14. Incubate the test plate at 37 ° C in a 5% CO2 incubator for 3 days.

Section C: Cell Fixation and Staining

5 At the end of the incubation period it will be necessary to fix the cells and do the SRB test as described below:

1. Transfer the plate from the incubator to the cell culture unit at 4 ° C; leave the cells for an hour.

10 2. Adherent cell lines: Fix the cells on the plate by carefully adding 30 µl of cold 50% v / v trichloroacetic acid (TCA BDH 102863H) to the cell culture medium already in the wells, so that the final concentration of TCA it is 10% v / v.

Cell lines in suspension: Fix the cells to the plate by carefully adding 30 µl of cold 15 80% v / v trichloroacetic acid (TCA BDH 102863H) to the cell culture medium already in the wells, so that the final concentration of TCA is of 16% v / v.

1.

Incubate at 4ºC for 1 hour.

2.

Immerse the plate in a plastic container containing distilled water, so that each well is

20 fill with water. Let soak for 1 minute. Shake the wash solution into the container and repeat this wash step four more times. Finally, shake off the wash solution and let it air dry.

3. When the wells are completely dry, add 100 µl of 0.4% w / v sulphorhodamine B (SRB Sigma S1402) in 1% v / v acetic acid to each well, and incubate at room temperature for 30 minutes.

4. Shake the SRB and wash four times by immersing the plates for 1 minute in 1% v / v acetic acid. Shake off the wash solution and allow to air dry.

5. When the wells are completely dry add 100 µl of 10 mM Tris base pH 10.5 (the pH is adjusted to 10.5 using a sodium hydroxide solution). Place on a plate shaker and mix 5 min. Read the plate at 564 nm using the data acquisition SPECTRAmax microplate spectrophotometer.

30 Test E

Clonogenic test results

Section A: Seeding the Test Plates

35 24-well plates (Falcon cat. No. 353047) from this test are seeded at the correspondingly determined seed density for each cell line.

Base agar: 40

1.

Melt 1.6% agar (Invitrogen Select Agar) in a microwave and cool to 40-42 ° C in a water bath.

2.

Heat the cell culture medium + 20% FBS + 2X of any other required cell culture supplement to 40-42 ° C in the water bath. Leave at least 30 minutes for the temperature to equilibrate.

45 3. Mix equal volumes of the two solutions to obtain 0.8% agar + medium + 10% FBS + 1X cell culture supplements.

4. Add 0.2 ml / well, allow to settle. Plates can be stored at 4 ° C for up to 1 week.

Superior agar: 50

1.

Melt 0.8% agar (Invitrogen Select Agar) in a microwave and cool to 40 ° C in a water bath.

2.

Heat the medium + 20% FBS + 2X of any other required cell culture supplement, at the same temperature.

55 3. Harvesting and counting the cells. All procedures associated with the harvesting and preparation of cell suspensions will be performed in a class II hood.

Four.

Dilute the cells in the medium to the appropriate seeding density.

5.

Appropriately mark the 24-well plates with base agar (if the plate is stored in the refrigerator,

remove the plate from 4 ° C approximately 30 minutes before proceeding to allow it to warm to room temperature).

6. For plating mix equal volumes of medium + 20% FBS + 2X cell culture supplements + cell solution and 0.8% soft agar in a capped 15 ml centrifuge tube; Mix gently and add 0.2 ml to each well in duplicate (usually plating is done in quadruplicate).

7. Incubate plates overnight at 37 ° C in a 5% CO2 incubator. 65

image175

1. Prepare the plate for the test compound (s) and then transfer the diluted compound to

the breadboard prepared in section A. 5

2. Dilute the test compound (s) to 120 µM in the cell culture medium in a separate tube, which will make an initial concentration of 40 µM.

The stock concentration of the test compound (s) is 10 mM; therefore, dilute 10 1: 83.3 to obtain a concentration of 120 µM.

3. Make 1: 2 dilutions of the test drug solution, 3 times from the initial 120 µM concentration, to prepare test drug concentrations at 20, 10 and 5 µM.

15 4. Transfer 200 µl of each test concentration to each well in quadruplicate. Column 6 contains 40 µM of the test compound (s). Column 5 contains 20 µM of test compound (s), column 4 contains 10 µM of test compound (s), and column 3 contains 5 µM of test compound.

20 5. DMSO controls same as drug: dilute 100% DMSO 1: 83.3 in medium. Pipette 200 µl to column 2 of the compound plate in quadruplicate, giving a final concentration of 0.4%.

6. Blank control: Pipette 200 µl of the blank medium per well to column 1 in quadruplicate.

25 7. Incubate the test plate at 37 ° C in a 5% CO2 incubator for 2-3 weeks.

Section C: Cell colony staining and counting

At the end of the incubation period it will be necessary to stain and count the cell colonies as described below.

1.

Mark the bottom of each well by dividing each well into at least four sections.

2.

Stain the plates with 0.2 ml of 0.005% crystal violet for 1 hour at 37 ° C and 5% CO2 in a humidified incubator.

35 3. Count colonies per well for each test group using a dissecting microscope.

Four.

Consider a group of cells as a colony, at least each colony must have 50 cells.

5.

Calculate the average number of colonies in each well per group, and calculate the% inhibition of cell colony formation produced by the test compound, using the formula T / C%, where T is the test group and C is control.

40

Test F

PP2C dephosphorylation test

45 10 ng of hyperphosphorylated AMPK trimer (α1 / β1 / у1) from Invitrogen (PV4672) were incubated in a buffer containing: 40 mM Hepes pH 7.45, 2 mM MnCl2, 0.5 mM DTT and 0.125 ng of recombinant PP2C-α1 (Abcam Ab51205), in the presence or absence of potential inhibitors of the enzyme reaction / interaction, in a total volume of 10 µl, for 20 minutes at 30 ° C. The reaction was terminated with the addition of 40 µl of stop solution containing 1% bovine serum albumin (BSA), 10 mM EDTA and Fospho-AMPKα antibody.

50 (Thr172) (Cell Signaling # 2531) at a 1/1000 dilution. Samples were transferred to a glutathione coated 96-well plate (Perforated # 15140) and incubated overnight at + 4 ° C. The plate was washed 3 x 200 µl in PBS / 0.05% Triton X-100. The plate was incubated with PBS / 1% BSA and horseradish peroxidase conjugated goat anti-rabbit antibody (Jackson Immunoresearch Laboratories Inc. # 111-035-003), at a dilution of 1/10000 for 2 h at temperature. environment. The plate was washed 3X200µl in PBS / 0.05% Triton X-100. The proof

55 was developed by adding 100 µl of the Liquid Substrate System for ELISA (Sigma, T0440) for 5-30 min. The development of the reaction was terminated by adding 25 µl 1 M to each well. The absorbance was measured at 450 nm, where the absorbance correlates with the amount of p-T172 AMPK.

Results

As illustrated in Figure 3, the compounds of Examples 1 and 2c have the ability to reduce PP2C-α1 mediated dephosphorylation of AMPK.

Claims (14)

image 1 1. A compound of formula I, image2 in which: A represents C (= N-W-D) or S; B represents S or C (-NH-W-D); when: A represents C (= N-W-D) and B represents S, then the dashed line between B and the N atom is a bond 15 single; or A represents S and B represents C (-NH-W-D), then the broken line between B and the N atom is a double bond; X represents -Q- [CRxRy] n-; W represents- [CRxRy] m- or -C (O) - [CRxRy] p-; Q represents a bond, -N (Ra) -, -S- or -O-; A1 to A5 respectively represent C (R1), C (R2), C (R3), C (R4) and C (R5), or, alternatively, up to two of A1 to A5 may independently represent N; D represents phenyl, pyridyl or pyrimidinyl optionally substituted with one or more R6 groups; Rx and Ry, each time used herein, are independently selected from H, Halogen, C16 alkyl (optionally substituted with one or more halogen atoms), aryl (optionally substituted with one or more halogen atoms), or Rx and Ry are bonded to form, together with the carbon atom to which they are attached, a 3 to 8-membered non-aromatic ring, optionally containing 1 to 3 heteroatoms selected from O, S, and N, which ring is itself optionally substituted with one or more substituents selected from halogen or C16 alkyl (optionally substituted with one or more atoms of 30 halogen); R1 to R5 independently represent H, halogen, -R7, -CF3, -CN, -NO2, -C (O) R7, -C (O) OR7, -C (O) N (R7a) R7b, -N (R7a ) R7b, -N (R7) 3+, -SR7, -OR7, -NH (O) R7, -SO3R7, aryl or heteroaryl (these same aryl and heteroaryl groups are optionally and independently substituted with one or more groups selected from halogen and R16), or any two of R1 to R5 that are adjacent to each other, are optionally linked to form, Together with two essential benzene ring atoms in the compound of formula I, a 3- to 8-membered aromatic or non-aromatic ring, optionally containing 1 to 3 heteroatoms selected from O, S, and N, which ring is the same optionally substituted with one or more substituents selected from halogen, -R7, -OR7, and = O; R6 independently represents, at each occurrence used herein, cyano, -NO2, 40 halogen, -R16, -OR8, -N (R8) C (O) R8, -NR9R10, -SR11, -Si (R12) 3, -OC (O) R13, -C (O) OR13, -C ( O) R14, -C (O) NR15aR15b, -S (O) 2NR15cR15d, aryl or heteroaryl (these same aryl and heteroaryl groups are optionally and independently substituted with one or more groups selected from halogen and R16), or any two R6 groups which are adjacent to each other, are linked to form, together with two essential benzene ring atoms in the compound of formula I, a 3- to 8-membered aromatic or non-aromatic ring, optionally containing 1 45 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted with one or more substituents selected from halogen, -R7, -OR7 and = O; R7, each time used herein, is selected from H or C1-C6 alkyl, C1-C6 cycloalkyl, aryl, and heteroaryl (wherein the last four groups are optionally substituted with one or more halogen atoms); R7a and R7b are independently selected from H, or C1-C6 alkyl, C1-C6 cycloalkyl, aryl, and heteroaryl, or R7a and R7b are optionally linked to form, together with the nitrogen atom to which they are attached, an aromatic ring or 3 to 8 membered non-aromatic, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted with one or more substituents selected from halogen, -R7, -OR7 and = O; Ra, R8, R9, R10, R11, R12, R13, R14, R15a, R15b, R15c, and R15d, each time used herein, independently represent H or R16; R16 represents, each time used herein, C16 alkyl optionally substituted with one or more halogen atoms; n represents 1 or 2; image3 fifteen 25 35 Four. Five 55 m represents 0, 1 or 2; p represents 0, 1 or 2; or a pharmaceutically acceptable salt or solvate, provided that:

(TO)

when D is phenyl, then at least one of A1 to A5 is not (C-H) and / or D is substituted with one or more R6 groups, and, with the additional condition that:

(B)

the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, is not 4-benzyl-5-picrillimino-1,2,4-thiadiazolidin-3-one.

2.

A compound according to claim 1, wherein:

at least one of A1 to A5 is not (C-H) and / or D is substituted with one or more -R6 groups; B represents S; Rx and Ry are independently selected from H, C16 alkyl (optionally substituted with one or more fluorine atoms), aryl (optionally substituted with one or more halogens, for example chlorine atoms) or Rx and Ry are linked to form, together with the carbon atom to which they are attached, an unsubstituted 3- to 6-membered non-aromatic ring; X represents -CH2-, -CH2CH2-, -O-CH2CH2-, -N (CH3) -CH2CH2-, -S-CH2CH2-, 1,1-cyclopropyl or -C (H) (4-chlorophenyl) -; at least one of R1 to R5, when present, represents halogen, -R7, -CF3, -CN, -C (O) R7, -C (O) OR7, -C (O) N (R7a) R7b, - N (R7) 3+, -SR7, -OR7 or -NH (O) R7, or any two of R1 to R5 that are adjacent to each other, are optionally bonded to form, together with two essential benzene ring atoms in the compound of formula I, a 3- to 8-membered aromatic or non-aromatic ring, optionally containing 1 to 3 heteroatoms selected from O, S and N, which ring is itself optionally substituted with one or more substituents selected from halogen, - R7, -OR7 and = O; R6 independently represents -R16, -CN, -OCF3, -NO2, -Br, -Cl, -F, -OR8, -NR9R10 or -SR11; n represents 1 or 2; m represents 0 or 1; p represents 0 or 1; and / or W represents a direct bond, -CH2-, -C (O) - or -C (O) CH2-.

3.

A compound according to claim 1, wherein:

at least one of R1 to R5, when present, represents 4H- [1,2,4] -triazolyl, -OR7, -Cl, -F, -CF3, -CN or -C (O) N (R7a) R7b ; each R6 independently represents -CN, -CF3, -OCF3, -F, or -Cl; and / or W represents -C (O) - or -C (O) CH2-.

Four.

A compound according to claim 1, which is selected from the group:

i) 5- (3,4-dichlorophenyl) imino-4 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazolidin-3-one; ii) 5- (3,4-dichlorophenyl) imino-4 - [(4-methoxyphenyl) methyl] -1,2,4-thiadiazolidin-3-one; iii) 4 - [(4-chlorophenyl) methyl] -5- (3,4-dichlorophenyl) imino-1,2,4-thiadiazolidin-3-one; iv) 5- (3,4-dichlorophenyl) imino-4 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazolidin-3-one; v) 5- (3,4-dichlorophenyl) imino-4 - [(3-fluorophenyl) methyl] -1,2,4-thiadiazolidin-3-one; vi) 5- (3,4-dichlorophenyl) imino-4- [phenyl) methyl] -1,2,4-thiadiazolidin-3-one; vii) 5- (3,4-dichlorophenyl) imino-4-phenethyl-1,2,4-thiadiazolidin-3-one; viii) 4- [2 - [(4-chlorophenyl) -methyl-amino] ethyl] -5- (3,4-dichlorophenyl) imino-1,2,4-thiadiaz-olidin-3-one; ix) 4- [2- (4-chlorophenyl) sulfanylethyl] -5- (3,4-dichlorophenyl) imino-1,2,4-thiadiazolidin-3-one; x) 3 - [[(5- (3,4-dichlorophenyl) imino-3-oxo-1,2,4-thiadiazolidin-4-yl] methyl] -N-methylbenzamide; xi) 5 - [(6-chloro -3-pyridyl) imino] -4 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazolidin-3-one; xii) 4 - [[4 - [(3,4-difluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] amino] benzonitrile; xiii) 4 - [(3,4-difluorophenyl) methyl] -5- [4- (trifluoromethyl) phenyl] imino-1,2,4-thiadiazolidin-3-one; xiv) 4 - [(3,4-difluorophenyl) methyl] -5- [4- (trifluoromethoxy) phenyl] imino-1,2,4-thiadiazolidin-3-one; xv) 3- [5- (3,4-dichlorophenyl) imino-3-oxo-1,2,4-thiadiazolidin-4-yl] methyl] benzonitrile; xvi) 5- (3,4-dichlorophenyl) imino-4 - [[4- (1,2,4-triazol-1-yl) phenyl] methyl] -1,2,4-thiadiazolidin-3-one; xvii) 4- [1- (4-chlorophenyl) cyclopropyl] -5- (4-chlorophenyl) imino-1,2,4-thiadiazolidin-3-one; xviii) 5 - [(4-chlorophenyl) methylimino] -4 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazolidin-3-one; N- [3-oxo-2 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazol-5-yl] benzamide; xix) 4-fluoro-N- [3-oxo-2 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazol-5-yl] benzamide; xx) 2- (4-fluorophenyl) -N- [3-oxo-2 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazol-5-yl] acetamide; xxy) 4-chloro-N- [2 - [(3,4-difluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxii) 4-chloro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxiii) 4-chloro-N- [2 - [(4-chlorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxiv) 4-chloro-N- [2- [2- (phenoxy) ethyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxv) 4-chloro-N- [2- [2 - [(4-chlorophenyl) -methyl-amino] ethyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; image4 xxvi) 4-chloro-N- [2- [2- (4-chlorophenyl) sulfanylethyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxvii) 3,4-dichloro-N- [2- [1- (4-fluorophenyl) cyclopropyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxviii) 3,4-dichloro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxix) N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] -4-methoxy-benzamide; Xxx) 2,6-dichloro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxxi) 2,4-dichloro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxxii) N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] -4- (trifluoromethoxy) -benzamide; xxxiii) N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] -3,5-bis (trifluoromethyl) -benzamide; xxxiv) 3,4-Difluoro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxxv) 2-chloro-6-fluoro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxxvi) 3,5-Difluoro-N- [2 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] benzamide; xxxvii) 5- (3,4-dichlorophenyl) imino-4- (2-phenoxyethyl) -1,2,4-thiadiazolidin-3-one; xxxviii) 5- (3,4-dichlorophenylamino) -2- (2-phenoxyethyl) - [1,2,4] thiadiazol-3-one; xxxix) 4-benzhydryl-5- (3,4-dichlorophenyl) imino-1,2,4-thiadiazolidin-3-one; 15 xl) 4-chloro-N- [4 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] benzamide; xli) 4-chloro-N- [4 - [(4-chlorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] benzamide; xlii) 4-chloro-N- [3-oxo-4 - [[3- (trifluoromethyl) phenyl] methyl] -1,2,4-thiadiazolidin-5-ylidene] -benzamide; xliii) N- [4 - [(3-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] -4- (trifluoromethyl) -benzamide; xliv) N- [4 - [(3-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] -3,5-bis (trifluoromethyl) benzamide; xlv) N- [4 - [(3,4-dichlorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] -3,4-difluorobenzamide; xlvi) 1,5- (3,4-dichlorophenylamino) -2- (4-methoxybenzyl) - [1,2,4] thiadiazol-3-one; xlvii) 1,5- (3,4-dichlorophenylamino) -2- (4-chlorobenzyl) - [1,2,4] thiadiazol-3-one; xlviii) 1,5- (3,4-dichlorophenylamino) -2- (3,4-difluorobenzyl) - [1,2,4] thiadiazol-3-one; xlix) 1,5- (3,4-dichlorophenylamino) -2- (3-fluorobenzyl) - [1,2,4] thiadiazol-3-one; 25 l) 1,5- (3,4-dichlorophenylamino) -2- (benzyl) - [1,2,4] thiadiazol-3-one; li) 5- (3,4-dichlorophenylamino) -2-phenethyl- [1,2,4] thiadiazol-3-one; lii) 2- [2 - [(4-chlorophenyl) -methyl-amino] ethyl] -5 - [(3,4-dichlorophenyl) amino] -1,2,4-thiadiazol-3-one; liii) 2- [2- (4-chlorophenyl) sulfanylethyl] -5 - [(3,4-dichlorophenyl) amino] -1,2,4-thiadiazol-3-one; liv) 3 - [[5 - [(4-chlorophenyl) amino] -3-oxo-1,2,4-thiadiazol-2-yl] methyl] -N-methylbenzamide; Iv) 5 - [(6-chloro-3-pyridyl) amino] -2 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazol-3-one; lvi) 2 - [(3,4-difluorophenyl) methyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one; lvii) 2 - [(3,4-difluorophenyl) methyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one; lviii) 5 - [(4-chlorophenyl) amino] -2- [1- (4-chlorophenyl) cyclopropyl] -1,2,4-thiadiazol-3-one; lix) 5 - [(3,4-dichlorophenyl) methylamino] -2 - [(3,4-difluorophenyl) methyl] -1,2,4-thiadiazol-3-one; 35 lx) 3,4-dichloro-N- [4 - [(4-fluorophenyl) methyl] -3-oxo-1,2,4-thiadiazolidin-5-ylidene] benzamide; lxy) 2 - [(4-methoxyphenyl) methyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one; lxii) 2 - [(4-chlorophenyl) methyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one; lxiii) 2 - [(3-fluorophenyl) methyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one; lxiv) 2- [phenylethyl] -5 - [[4- (trifluoromethyl) phenyl] amino] -1,2,4-thiadiazol-3-one; lxv) 2 - [(4-methoxyphenyl) methyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one; lxvi) 2 - [(4-chlorophenyl) methyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one; lxvii) 2 - [(3-fluorophenyl) methyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one; lxviii) 2- [phenylethyl] -5 - [[4- (trifluoromethoxy) phenyl] amino] -1,2,4-thiadiazol-3-one; and lxix) 4 - [[2 - [(3,4-difluorophenyl) methyl] -3-oxo-1,2,4-thiadiazol-5-yl] amino] benzonitrile. Four. Five

5.

A compound as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate, but without condition (B), for use as a pharmaceutical.

6.

A pharmaceutical formulation including a compound as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate, but without condition (B), in admixture with a pharmaceutically adjuvant, diluent or carrier acceptable.

7.

A combination product comprising:

(A) a compound of formula I as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate, but without condition (B); and (B) another therapeutic agent useful in the treatment of cancer, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 8. A combination product according to claim 7 comprising: a pharmaceutical formulation including a compound of formula I as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate, but without condition (B), another therapeutic agent useful in the treatment of cancer, and a pharmaceutically acceptable adjuvant, diluent, or carrier; or image5 a parts kit comprising the components: (a) a pharmaceutical formulation including a compound of formula I as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate, but without condition (B), in admixture with an adjuvant, a pharmaceutically acceptable diluent or carrier; and 5 (b) a pharmaceutical formulation that includes another therapeutic agent useful in the treatment of cancer in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, said components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other. 9. A combination product comprising a kit of parts according to claim 8, wherein components (a) and (b) are suitable for their sequential, separate and / or simultaneous use in the treatment of cancer. A combination product according to any one of claims 7 to 9, wherein the other therapeutic agent is selected from:

(i)

a cytostatic agent or a pharmaceutically acceptable salt, solvate or derivative thereof;

(ii)

an angiogenesis inhibitor or a pharmaceutically acceptable salt, solvate or derivative thereof;

(iii) tamoxifen or a pharmaceutically acceptable salt, solvate or derivative thereof; (iv) an aromatase inhibitor or a pharmaceutically acceptable salt, solvate or derivative thereof;

(v)

trastuzumab (Herceptin) or another antibody that is helpful in treating cancer;

(saw)

a tyrosine kinase inhibitor, or a pharmaceutically acceptable salt, solvate or derivative thereof;

(vii) a glitazone or a pharmaceutically acceptable salt, solvate or derivative thereof; (viii) biguanides or a pharmaceutically acceptable salt, solvate or derivative thereof; (ix) a statin or a pharmaceutically acceptable salt, solvate or derivative thereof; (X) a mammalian rapamycin target activity inhibitor (mTOR) or a pharmaceutically acceptable salt, solvate or derivative thereof; (xi) an oligomycin, or a pharmaceutically acceptable salt, solvate or derivative thereof; (xii) AICAR (aminoimidazole carboxamide ribonucleotide) or a pharmaceutically acceptable salt, solvate or derivative thereof; (xiii) a peroxisome proliferator activated receptor (PPAR) agonist or a pharmaceutically acceptable salt, solvate or derivative thereof; (xiv) A-769662 (6,7-dihydro-4-hydroxy-3- (2'-hydroxy [1,1'-biphenyl] -4-yl) -6-oxo-thieno- [2,3-b ] pyridine-5-carbonitrile) or a pharmaceutically acceptable salt, solvate or derivative thereof; 45 (xv) D942 (5- (3- (4- (2- (4-fluorophenyl) ethoxy) -phenyl) propyl) furan-2-carboxylic acid) or a pharmaceutically functional salt, solvate or derivative thereof acceptable; (xvi) AM251 (1- (2,4-dichlorophenyl) -5- (4-iodophenyl) -4-methyl-N- (1-piperidyl) pyrazole-3-carboxamide) or a salt, a solvate or a pharmaceutically acceptable pharmaceutically functional derivative thereof; (xvii) a SIRT1 activator or a pharmaceutically acceptable salt, solvate or derivative thereof; me (xviii) salidroside or a pharmaceutically acceptable salt, solvate or derivative thereof. 11. The use of a compound of formula I as defined in any one of claims 1 to 4 or a 55 pharmaceutically acceptable salt or solvate, but without condition (B), or a combination product as defined in any one of claims 7 to 10, for the preparation of a medicament for the treatment of cancer.

12.

A compound as defined in any one of claims 1 to 4 or a pharmaceutically acceptable salt or solvate, but without condition (B), or a combination product as defined in any one of claims 7 to 10 , for use in the treatment of cancer.

13.

A combination product as according to claim 9, a use as according to claim 11 or a compound or a combination product according to claim 12, wherein:

The cancer is a solid tumor or a hematopoietic tumor; image6 cancer is a solid tumor of the colon, breast, or prostate; the cancer is of the breast; or the cancer is a hematopoietic tumor which is a leukemia. The use of a compound of formula I as defined in any one of claims 1 to 4 or a pharmaceutically acceptable salt or solvate, but without condition (B), for the preparation of a medicament for the treatment diabetes. 15. A compound as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate, but without condition (B), for use in the treatment of diabetes. 16. A process for the preparation of a compound of formula I as defined in any one of claims 1 to 4, (I) for compounds of formula I in which A represents S, cyclization of a compound of formula IIa, image7 wherein A1 to A5, X, W and D are as defined in claim 1; (ii) for compounds of formula I in which A represents S, W represents - [CRxRy] m- and m represents 1 or 2, the reaction of a compound of formula III, image8 Wherein A1 to A5 and X are as defined in claim 1, with a compound of formula IV, L2-W1-D IV wherein L2 represents a suitable leaving group, W1 represents- [CRxRy] m- wherein m represents 1 and D is 30 as defined in claim 1; (iii) for compounds of formula I where A represents S, W represents- [CRxRy] m and m represents 0, the reaction of a compound of formula III as defined hereinbefore with a compound of formula V , 35 L3-D V wherein L3 is a suitable leaving group and D is as defined in claim 1; (iv) for compounds of formula I in which A represents S, W represents -C (O) - [CRxRy] p-, the reaction of a compound of formula III as defined hereinbefore with a compound of formula VI, L4-W2-D VI wherein L4 is a suitable leaving group u -OH, W2 represents -C (O) - [CRxRy] p-, and D is as defined in claim 1; (v) for compounds of formula I where A represents S, and Q is a bond, -O- or -S-, the reaction of a compound of formula VII, image9 wherein W and D are as defined in claim 1, with a compound of formula VIII, image10 wherein A1 to A5, n, Rx and Ry are as defined in claim 1, L5 is a suitable leaving group and Q is a bond, -O- or -S-; (vi) for compounds of formula I where W is - [CRxRy] m-, the reaction of a compound of formula IX, image11 wherein L6 represents a suitable leaving group and A1 to A5 and X are as defined in claim 1, with a compound of formula X, H2N-W-D X wherein W and D are as defined in claim 1; and vii) for compounds of formula I in which B represents S, cyclization of a compound of formula IIb, image12 wherein A1 to A5, X, W and D are as defined in claim 1 above.